Rheumatoid Arthritis: Ishiguro N

Ishiguro N. · Department of Orthopedic Surgery, Nagoya University School of Medicine. · Clin Calcium. · Pubmed #19252244 No free full text.

Abstract: Rheumatoid arthritis (RA) is a polyarticular joint disease. The inflammatory process is characterized by infiltration of inflammatory cells into the joints, leading to proliferation of synoviocytes and destruction of cartilage and bone. The Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases. It had been well recognized that MMP play major roles in the cartilage breakdown in RA and OA. Moreover ADAM-TS-1, -4, -5 have aggrecanase activity, and also involve the cartilage degradation in RA and OA. Of course they contribute the cartilage homeostasis in healthy subjects. Failure to regulate the synthesis, activation and inhibition of the proteinases finally leads to cartilage destruction. Aggrecan and type II collagen are major components in cartilage matrix. Cleavage of aggrecan by aggrecanase and that of collagen by collagenase are critical steps for degradation of articular cartilage in RA. To prevent the cartilage damage, inflammatory synovitis should be suppressed in early stage.

Ishiguro N. · Department of Orthopedic Surgery, Nagoya University, Graduate School & Faculty of Medicine. · Nippon Rinsho. · Pubmed #17642231 No free full text.

Abstract: Rheumatoid arthritis (RA) is characterized with inflammation of joints and damage of joints tissue. Therefore it induced the disability and handicap in RA patients. This paper described the mortality and functional prognosis in rheumatoid arthritis patients. The numerous number of studies concerning on mortality in RA patients revealed that RA is not benign disease, provided excess rate of mortality compared to normal population. The degree of joints damages was conventionally assessed with radiographic images. So X-P images reflects the course of disease activity and disabilities in RA. The previous assessments with X-P images revealed that the bone erosions and joint space narrowing occurred within two years after onset of RA among approximately 70 % patients. Now it is considered that the joint destruction induced early stage of RA, therefore the promising therapy are needed for the patients who are at risk of poor prognosis. It should be investigated whether the biologic drugs, including TNFalpha inhibitor can alter the mortality and functional prognosis in RA patients.

Ishiguro N. · Orthopaedic Surgery, Graduate School of Medicine, Nagoya University. · Nippon Rinsho. · Pubmed #16164215 No free full text.

Abstract: The establishment of better methods than the conventional radiological examination in the management of rheumatoid arthritis is one of the key issues to be achieved in near future. The conventional X-ray examinations are not so sensitive or specific to early pathologies of inflammation and subtle changes. However, from the economical and clinical point of view, still plane X-ray images have several advantage. Several grading system including Steinbrocker, Larsen grade and Sharp score had been developed. Magnetic resonance image offers improved sensitivity to early inflammation of synovial tissue and bone destructive changes in the joints in RA patients. There are clear evidence for MRI synovitis representing true synovial inflammation. The clinician who intends to manage the inflammatory joint diseases should have the knowledge of these evaluation systems.

Ishiguro N. · Department of Orthopaedic Surgery, Nagoya University Graduate School & Faculty of Medicine. · Nippon Rinsho. · Pubmed #15799379 No free full text.

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Koike T, Harigai M, Inokuma S, Inoue K, Ishiguro N, Ryu J, Takeuchi T, Tanaka Y, Yamanaka H, Fujii K, Freundlich B, Suzukawa M. · Japan College of Rheumatology Etanercept Post-Marketing, Surveillance Committee, Wyeth K.K., Medical Affairs, Osaka, Japan. · J Rheumatol. · Pubmed #19332630 No free full text.

Abstract: OBJECTIVE: Postmarketing surveillance (PMS) was conducted evaluating safety and effectiveness of etanercept (ETN; Enbrel) in Japan, following all patients with rheumatoid arthritis (RA) during the conditional approval period of ETN. METHODS: Registration of patients from 1,334 medical sites was conducted between March 2005 and April 2007. Patients were followed for 24 weeks; data regarding patients' background, safety, and effectiveness was recorded centrally. Adverse events (AE) and adverse drug reactions (ADR) were coded using the Medical Dictionary for Regulatory Activities. Effectiveness was measured using the Disease Activity Score 28 (DAS28). RESULTS: Of 14,369 patients registered, data collection and evaluation for 7,091 patients by March 2006 is reported. At least 1 AE was observed for 2,173 patients (30.6%); 60% of AE occurred within 8 weeks of starting ETN. Most frequent AE were injection site reaction (n = 377, 5.3%) and rash (n = 228, 3.2%). Serious AE occurred in 403 patients (5.7%); most frequent were pneumonia (n = 59, 0.8%) and interstitial lung disease (n = 42, 0.6%). Pneumonia was the most common specifically important ADR (n = 102, 1.4%). Mean baseline DAS28 was 6.0, which reduced to 4.4 within 4 weeks, and to 3.9 within 24 weeks. The proportion of patients having good or moderate EULAR response measured by DAS28 was 84.1% at Week 24. Effectiveness rates were more favorable in patients concomitantly using methotrexate. Good or moderate EULAR response rate among patients switched from infliximab was 84.9%. CONCLUSION: This extensive observational trial, including all patients with RA in Japan taking ETN, found ETN to be both effective and well tolerated by Japanese patients with RA. Trial registration: clinicaltrials.gov identifier NCT00503503.

Hirano Y, Kojima T, Kanayama Y, Ishikawa H, Ishiguro N. · Department of Orthopaedic Surgery and Rheumatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan, · Mod Rheumatol. · Pubmed #19266254 No free full text.

Abstract: We report a case of a 65-year-old man with rheumatoid arthritis. The patient was treated with methotrexate and prednisolone, but the disease activity remained high. A tuberculin skin test was positive. After antituberculosis (TB) chemoprophylaxis with isoniazid for four weeks, infliximab was administered. Chemoprophylaxis was continued for nine months. Active lung TB was diagnosed at 17 months after the cessation of isoniazid, namely at 27 months after starting infliximab treatment. This case report shows that TB can manifest after chemoprophylaxis in patients treated with antitumor necrosis factor agents.

Sugiura F, Kojima T, Oguchi T, Urata S, Yuzawa Y, Sakakibara A, Hayashi H, Nishimoto N, Ishiguro N. · Department of Orthopedic Surgery, Anjo Kosei Hospital, 28 Higashihiroaze, Anjo-cho, Anjo, Aichi 466-8602, Japan. · Mod Rheumatol. · Pubmed #18987779 No free full text.

Abstract: We report a case of peripheral neuropathy and skin ulcer in a patient with rheumatoid arthritis (RA) who received tocilizumab. A 65-year-old woman with a 20-year history of RA participated in a tocilizumab clinical trial. She received a single dose of 8 mg/kg tocilizumab intravenously. The following day the patient started to experience numbness and purpura in all four extremities. The purpura of her left lower limb became necrotic, and a skin ulcer appeared 3 weeks later. Steroid-pulse treatment was initiated 12 weeks after tocilizumab administration, with the result that the numbness improved, and the skin ulcers showed complete epithelialization.

Takeuchi T, Tatsuki Y, Nogami Y, Ishiguro N, Tanaka Y, Yamanaka H, Kamatani N, Harigai M, Ryu J, Inoue K, Kondo H, Inokuma S, Ochi T, Koike T. · Division of Rheumatology and Clinical Immunology, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama 350-8550, Japan. · Ann Rheum Dis. · Pubmed #17644554 links to  free full text

Abstract: OBJECTIVES: A large-scale postmarketing surveillance (PMS) study was carried out to determine the safety profile of infliximab in Japanese patients with rheumatoid arthritis (RA). METHODS: The PMS study was performed for all patients with RA who were treated with infliximab. They were consecutively registered in the PMS study at the initiation of infliximab treatment and were prospectively monitored with all adverse events noted for a period of 6 months. All case reports, which include safety-related events, were collected monthly. RESULTS: Adverse drug reactions (ADRs) were assessed for 6 months in 5000 patients who were consecutively enrolled in the PMS study. The incidence rates of total and serious ADRs were 28.0% and 6.2%, respectively. "Infections" or "respiratory disorders" were most commonly observed among serious ADRs. Bacterial pneumonia developed in 2.2%, tuberculosis in 0.3%, suspected Pneumocystis jiroveci pneumonia (PCP) in 0.4% and interstitial pneumonitis in 0.5%. Bacterial pneumonia (for which individuals of male gender, of older age and those with advanced rheumatoid arthritis and comorbid respiratory disease were most at risk) began to develop immediately after the start of treatment, while tuberculosis, PCP and interstitial pneumonitis developed about 1 month later. Serious infusion reactions were observed in 0.5% and were more likely to occur in patients who had participated in previous clinical trials of infliximab. CONCLUSION: This postmarketing surveillance study of patients treated with infliximab showed that infliximab in combination with low-dose MTX was well tolerated in Japanese patients with active RA.

Yamamoto H, Muramatsu H, Nakanishi T, Natori Y, Sakuma S, Ishiguro N, Muramatsu T. · Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan. · Biochem Biophys Res Commun. · Pubmed #17094944 No free full text.

Abstract: Intraperitoneally administered chondroitin sulfate E inhibited the development of antibody-induced arthritis, a model of rheumatoid arthritis, while chondroitin 4-sulfate showed no effects. Chondroitin sulfate E inhibited in vitro differentiation of osteoclasts, which play key roles in the etiology of rheumatoid arthritis. One of the targets of chondroitin sulfate E is midkine, a heparin-binding growth factor or cytokine. Indeed, a chimeric-type siRNA for midkine inhibited the development of antibody-induced arthritis and adhesion of the omentum to the injured abdominal wall. These results indicate the significance of midkine as a molecular target to treat or prevent rheumatoid arthritis and adhesion after surgery, and the utility of chondroitin sulfate E to inhibit midkine in vivo.

Sugiura F, Kojima T, Oba M, Tsuchiya H, Ishiguro N. · Department of Orthopaedic Surgery, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. · Mod Rheumatol. · Pubmed #17029063 No free full text.

Abstract: Here we report on two cases of anaphylactic reaction following infliximab infusion in patients with active rheumatoid arthritis (RA). Both individuals had received infliximab treatment during a clinical trial approximately 2 years prior to further therapy; subsequent infusion of this agent led to anaphylactic reactions in both cases. In light of these findings, we recommend that future treatments with infliximab in RA patients who have previously received this agent should be carefully monitored.

Zhuo L, Kanamori A, Kannagi R, Itano N, Wu J, Hamaguchi M, Ishiguro N, Kimata K. · Institute for Molecular Science of Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan. · J Biol Chem. · Pubmed #16702221 links to  free full text

Abstract: CD44-hyaluronan (HA) interaction is involved in diverse physiological and pathological processes. Regulation of interacting avidity is well studied on CD44 but rarely on HA. We discovered a unique covalent modification of HA with a protein, SHAP, that corresponds to the heavy chains of inter-alpha-trypsin inhibitor family molecules circulating in blood. Formation of the SHAP.HA complex is often associated with inflammation, a well known process involving the CD44-HA interaction. We therefore examined the effect of SHAP on the CD44-HA interaction-mediated lymphocyte adhesion. Under both static and flowing conditions, Hut78 cells (CD44-positive) and CD44-transfected Jurkat cells (originally CD44-negative) adhered preferentially to the immobilized SHAP.HA complex than to HA. The enhanced adhesion is exclusively mediated by the CD44-HA interaction, because it was inhibited by HA, but not IalphaI, and was completely abolished by pretreating the cells with anti-CD44 antibodies. SHAP appears to potentiate the interaction by increasing the avidity of HA to CD44 and altering their distribution on cell surfaces. Large amounts of the SHAP.HA complex accumulate in the hyperplastic synovium of rheumatoid arthritis patients. Leukocytes infiltrated to the synovium were strongly positive for HA, SHAP, and CD44 on their surfaces, suggesting a role for the adhesion-enhancing effect of SHAP in pathogenesis.

Ishiguro N, Kojima T. · Nagoya University, Graduate School & Faculty of Medicine, Department of Orthopaedic Surgery. · Clin Calcium. · Pubmed #15775147 No free full text.

Abstract: Rheumatoid arthritis (RA) is characterized as inflammatory disease associated with cartilage degradation and subchondral bone erosion. RA is an autoimmune disease that has genetic and environmental backgrounds. The preservation of a functional articular cartilage enables the survival of a tissue that covers articulating surfaces in affected joints. The extracellular matrix of articular cartilage provides this tissue with its gprimary strength, resistance to deformation, and ability to dissipate load in the joint. Many research had been designed for trying to measure the remodeling and pathologic events in RA caritlage. The many matrix molecules, and their degradation products, are released from cartilage and bone and can be detected biochemically and immunologically in the serum and Joint fluids. Before evaluating the data of biomarkers revealed in pathologic conditions such as RA and OA, our skeletal system is built and maintained by a balance between synthesis and degradation. Furthermore this balance varies considerably from one person to another. It is nortworhy that the off-balance between synthesis and degradation lead to cartilage destruction. The use of many of the biomarker assays for matrix turnover offers the evidences to evaluate whether the treatments designed to inhibit the joint damage may successfully work in specific RA patients.

Oguchi T, Ishiguro N. · Department of Orthopaedic Surgery, Nagoya University School of Medicine, Nagoya, Japan. · Connect Tissue Res. · Pubmed #15763928 No free full text.

Abstract: This study compares the regulation of three isoforms of hyaluronan synthase (HAS1, HAS2, and HAS3) transcripts and hyaluronan (HA) production by cytokines in human synovial fibroblastic cells derived from tissue from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Levels of HAS mRNA of the cells with or without stimulation were detected using a real-time fluorescence polymerase chain reaction detection system. Concentrations of HA in the culture supernatants of the cells were measured by a sandwich binding protein assay. Molecular weight of HA was evaluated by agarose gel electrophoresis. The relative proportions of the expression pattern of HAS isoforms was similar between RA and OA tissue-derived cells. HAS1 mRNA was upregulated by transforming growth factor-beta and HAS3 mRNA was upregulated by interleukin-1beta and somewhat by tumor necrosis factor-alpha in the RA cells. HAS2 remained unchanged. Differences in the expression pattern of HAS1, HAS2, and HAS3 mRNA by cytokines suggest that these three isoforms are independently and differentially regulated, and each isoform of HAS may have a different role in arthritic joint disease.

Matsuyama Y, Kawakami N, Yoshihara H, Tsuji T, Kamiya M, Yukawa Y, Ishiguro N. · Department of Orthopedic Surgery, School of Medicine, Nagoya University School, Nagoya, Japan. · J Spinal Disord Tech. · Pubmed #15699794 No free full text.

Abstract: OBJECTIVE: This is a retrospective study of the outcome of occipitothoracic fusion surgery in rheumatoid arthritis (RA) patients with destruction of the cervical spine, designed to assess the efficacy of halo vest before surgery, the postoperative outcome, and the activities-of-daily living (ADL) problems associated with surgical management. There have been no reports regarding these issues, including surgical effect on subjacent vertebrae. METHODS: This study included 20 RA patients with destruction of the cervical spine. All patients underwent preoperative halo vest followed by occipitothoracic fusion with an average follow-up of 5 years. The long-term clinical outcomes were analyzed using a modified Ranawat classification. RESULTS: Before halo application, the neurologic status was assessed as IIIC in 15 patients and IIIB in 5 patients. After halo application, the neurologic status improved in all patients: IIIA in 12 patients and IIIB in 8 patients. After surgery, the neurologic status did not improve in six of the eight IIIB patients but improved to IIIA in two patients. Of the 12 IIIA patients, the neurologic status improved to II in 6 patients but did not improve in the other 6 patients. Patient satisfaction was excellent for 14 patients, good for 3 patients, and fair for only 3 patients (1 had difficulty drinking, another had back pain, and the last had low back pain associated with a compression fracture of the lumbar spine). CONCLUSIONS: We have performed occipitothoracic fusion surgery in RA patients with destruction of the cervical spine. Preoperative halo vest was very effective for improving the neurologic status, for the general condition, and for an optimal sagittal alignment. Occipitothoracic fusion using unit rods gave satisfactory long-term clinical results compared with the prognosis of patients in whom the disease follows its natural course.

Maruyama K, Muramatsu H, Ishiguro N, Muramatsu T. · Department of Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. · Arthritis Rheum. · Pubmed #15146411 links to  free full text

Abstract: OBJECTIVE: Midkine (MK), a heparin-binding growth factor, promotes growth, survival, and migration of various cells. The essential role of MK in migration of inflammatory cells has been shown using mice deficient in the MK gene (Mdk(-/-) mice). We undertook this study to investigate the role of MK in the pathogenesis of rheumatoid arthritis (RA). METHODS: MK levels in specimens from patients were determined by enzyme-linked immunosorbent assay, and localization of MK was revealed by immunohistochemical analysis. Susceptibility to antibody-induced arthritis was compared between Mdk(-/-) and wild-type (WT) mice. Osteoclast differentiation was monitored using macrophage-like cells isolated from human synovial tissue and macrophages from mouse bone marrow. RESULTS: MK levels in sera and synovial fluid were increased in most RA patients, indicating a strong correlation between MK expression and RA. MK was expressed in macrophage-like cells and fibroblast-like cells in synovial membranes from the patients. In antibody-induced arthritis, Mdk(-/-) mice seldom developed the disease, while most of the WT mice did. Administration of MK to the Mdk(-/-) mice increased the frequency of antibody-induced arthritis. Migration of inflammatory leukocytes to the synovial membranes in the disease model was suppressed in the Mdk(-/-) mice. Furthermore, MK was found to promote the differentiation of osteoclasts from macrophages. CONCLUSION: MK participates in each of the two distinct phases of RA development, namely, migration of inflammatory leukocytes and osteoclast differentiation, and is a key molecule in the pathogenesis of RA.

Uchibori M, Nishida Y, Tabata I, Sugiura H, Nakashima H, Yamada Y, Ishiguro N. · Department of Orthopaedic Surgery, Aichi Prefectural Hospital, Aichi, Japan. · J Rheumatol. · Pubmed #14705229 No free full text.

Abstract: OBJECTIVE: Pigmented villonodular synovitis (PVNS) is an uncommon idiopathic, proliferative synovial disease. Since matrix metalloproteinases (MMP) are assumed to play an important role in the pathogenesis of PVNS, we examined the expression and activity of MMP and tissue inhibitor of metalloproteinases (TIMP) in PVNS. METHODS: Synovial tissue samples were obtained from 10 patients with PVNS (knee 8, ankle 2) and 4 patients each with rheumatoid arthritis (RA) or osteoarthritis (OA) for comparison. Protein deposition and mRNA expression were determined by conventional immunohistochemical studies and reverse transcription-polymerase chain reaction (RT-PCR), respectively. Gelatin zymography was performed for detection of gelatin-degrading activity. The quantity of MMP and TIMP was measured by ELISA. RESULTS: Intense immunostaining for MMP-1 was detected in both the multinucleated giant cells and mononuclear cells, whereas TIMP-1 was weakly positive. MMP-9 immunostained predominantly in the multinucleated cells, whereas other MMP and TIMP were weakly detected. RT-PCR analysis showed that mRNA expression of MMP-9 was stimulated in PVNS, whereas MMP-2 mRNA was not, compared to RA or OA. The gelatin zymogram indicated protease activities predominantly at 92 kDa and 67 kDa. In accord with the immunostaining results, the amount of MMP-1 and MMP-9 protein was significantly higher than that of TIMP-1 and MMP-2, respectively. CONCLUSION: We characterized the expression and activity of MMP in PVNS and observed that PVNS tissues predominantly produce MMP-1 and MMP-9. Given that PVNS occasionally induces joint destruction, stimulated expression of MMP-1 and MMP-9 may contribute to the invasive activity and the bone and cartilage loss in PVNS.

Yingsung W, Zhuo L, Morgelin M, Yoneda M, Kida D, Watanabe H, Ishiguro N, Iwata H, Kimata K. · Institute for Molecular Science of Medicine and Matrix Glycoconjugate Group, Research Center for Infectious Disease, Aichi Medical University, Nagakute, Aichi 480-1195, Japan. · J Biol Chem. · Pubmed #12799384 links to  free full text

Abstract: We previously found that a covalent complex of SHAPs (serum-derived hyaluronan-associated proteins), the heavy chains of inter-alpha-trypsin inhibitor family molecules, with hyaluronan (HA) is accumulated in synovial fluid of patients with rheumatoid arthritis, and the complex is circulated in patient plasma at high concentrations. How the SHAP-HA complex participates in this disease is unknown. To address this question, it is essential to clarify the structural features of this macromolecule. The SHAP-HA complex purified from synovial fluid of the patients by three sequential CsCl isopycnic centrifugations was heterogeneous in density, and the fractions with different densities had distinct SHAP-to-HA ratios. Agarose gel electrophoresis and column chromatography revealed that there was no apparent difference in the size distribution of HA to which SHAPs were bound between the fractions with different densities. The SHAP-HA complex in the higher density fraction had fewer SHAP molecules per HA chain. Therefore, the difference between the fractions with different densities was due to a heterogeneous population of the SHAP-HA complex, namely the different number of SHAP molecules bound to an HA chain. Based on the SHAP and HA contents of the purified preparations, we estimated that an HA chain with a molecular weight of 2 x 106 has as many as five covalently bound SHAPs, which could give a proteinaceous multivalency to HA. Furthermore, we also found that the SHAP-HA complex tends to form aggregates, judging from the migration and elution profiles in agarose gel electrophoresis and gel filtration, respectively. The multivalent feature of the SHAP-HA complex was also confirmed by the negative staining electron micrographic images of the purified fractions. Taken together, those structural characteristics may underlie the aggregate-forming and extracellular matrix-stabilizing ability of the SHAP-HA complex.

Saito S, Kondo S, Mishima S, Ishiguro N, Hasegawa Y, Sandell LJ, Iwata H. · Department of Surgery, Nagoya University School of Medicine, Japan. · J Bone Joint Surg Br. · Pubmed #12358374 links to  free full text

Abstract: We have measured the concentration of cartilage-derived retinoic-acid-sensitive protein (CD-RAP) in synovial fluid (SF) from the knees of 49 patients with osteoarthritis (OA) and 79 with rheumatoid arthritis (RA) in order to investigate the correlation between the type of joint disease and level of CD-RAP. The mean concentration of CD-RAP in synovial fluid was significantly higher in OA than in RA. The level of CD-RAP in the group of patients with mild OA was significantly higher than in the moderate or severe groups and that in the group with mild RA was also significantly higher than in the other RA groups and decreased with progression of the disease. Immunohistochemical studies showed expression of CD-RAP in the cytoplasm of chondrocytes in newly-formed fibrocartilage. Since CD-RAP is mainly produced in young and proliferating chondrocytes, our results suggest that the level of CD-RAP in synovial fluid reflects remodelling of articular cartilage and may be used as a marker to estimate objectively the restorative reaction of chondrocytes.

Ishiguro N, Ito T, Oguchi T, Kojima T, Iwata H, Ionescu M, Poole AR. · Department of Orthopaedic Surgery, Nagoya University, School of Medicine, Japan. · Arthritis Rheum. · Pubmed #11710706 No free full text.

Abstract: OBJECTIVE: To determine interrelationships in matrix turnover in articular cartilage and joint inflammation in rheumatoid arthritis (RA). METHODS: Synovial fluid was obtained from the knees of 63 RA patients; radiographs were evaluated to determine the RA stage. Concentrations of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), the 846 epitope, and the keratan sulfate (KS) epitope of aggrecan, the C-propeptide of cartilage type II procollagen (CPII; biosynthetic marker), the cleavage of type II collagen by collagenase (CIIC; generated neoepitope), and polymorphonuclear leukocyte elastase (PMNE; inflammation marker) were measured by immunoassay. Concentrations of the unsaturated disaccharides of hyaluronic acid (delta di-HA) and the proteoglycan glycosaminoglycan disaccharides of chondroitins 4 and 6 sulfate (delta di-C4S and delta di-C6S) were determined by high-performance liquid chromatography. RESULTS: MMP-3 was markedly increased in RA compared with osteoarthritis. Increases in TIMP-1 in RA were less pronounced and were inversely correlated with MMP-3 levels. CIIC was reduced in RA, as was the release of the KS epitope and delta di-C6S. In contrast, delta di-C4S and the 846 epitope were up-regulated. PMNE levels correlated with the 846 epitope and delta di-C4S, and more strongly with TIMPs 1 and 2. The changes may signify attempts at control of proteolysis in parallel with increased aggrecan turnover, which would favor matrix assembly. PMNE also correlated with MMP-9, and MMP-9 correlated with CPII. The delta di-HA level was decreased in RA and was inversely correlated with CPII and MMP-9 as well as with MMPs 2 and 3. In contrast, delta di-HA was directly correlated with TIMP-1 and the 846 epitope. These observations suggest that HA and PMNs may be involved in the control of proteolysis and cartilage proteoglycan assembly. CONCLUSION: Our observations provide new insights into the complex changes in cartilage turnover and PMN influx in RA joints.

Takagi H, Ishiguro N, Iwata H, Kanamono T. · Department of Orthopedic Surgery, Nagoya University School of Medicine, Japan. · J Rheumatol. · Pubmed #10914844 No free full text.

Abstract: OBJECTIVE: To investigate estrogen receptor (ER) microsatellite allele frequencies in patients with rheumatoid arthritis (RA), and possible associations of ER microsatellites with osteoporosis and disease progression. METHODS: We typed 144 Japanese females with RA and 200 healthy postmenopausal Japanese controls for ER microsatellites by polymerase chain reaction methods using fluorescent labeled primer and semiautomatic genotyping. Bone mineral density (BMD) of patients was measured in the spine by dual energy x-ray absorptiometry, and recent radiographs of the hands and wrists were scored according to the method described by Sharp, et al. RESULTS: The ER genotype was classified according to number of dinucleotide (thymine-adenine, TA) repeats between 10 and 27. The frequency of allele 14 (14 repeats of TA) was significantly increased in patients versus controls. No association of ER microsatellites with osteoporosis or radiographic progression in the RA patients was noted. CONCLUSION: These results suggest that a genetic variation at the ER locus may be associated with other pathogenetic factors in patients with rheumatoid arthritis, but not with BMD and disease aggressiveness.

Wang LR, Ishiguro N, Yamada E, Nishida Y, Sato K, Iwata H. · Department of Orthopaedic Surgery, Nagoya University School of Medicine, Japan. · Am J Chin Med. · Pubmed #10467454 No free full text.

Abstract: Da-Fang-Feng-Tang (DFFT), which is believed to be effective for treating human rheumatoid arthritis (RA), was given to DBA/1 mice at the onset of type II collagen-induced arthritis (CIA) to examine its effect. Granules of the crude DFFT extract were administered by gastric gavage at a dose of 1.6 g/kg/day for 12 weeks, starting the day CIA began. The levels of anticollagen IgG antibody were significantly decreased in the sera of the DFFT-treated group compared with the control group from weeks 2 to 7 after the onset of CIA. The severity of arthritis in the DFFT-treated group was markedly alleviated when compared with the control group. In addition, histological examination of the DFFT-treated group showed less cartilage and bone erosion. These results suggest that administration of DFFT suppressed the development of CIA in mice and support the belief that DFFT is effective in treating human RA.

Kida D, Yoneda M, Miyaura S, Ishimaru T, Yoshida Y, Ito T, Ishiguro N, Iwata H, Kimata K. · Institute for Molecular Science of Medicine, Aichi Medical University, Nagakute, Japan. · J Rheumatol. · Pubmed #10381035 No free full text.

Abstract: OBJECTIVE: To investigate serum derived hyaluronan (HA) associated protein-hyaluronan (SHAP-HA) complex in sera from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) and determine levels of the complex in comparison with those of hyaluronan (HA), in order to assess the role of the complex as an indicator of joint inflammation. METHODS: ELISA and HA binding assays were used for quantitation of the SHAP-HA complex and HA levels in serum samples from 142 patients (114 with RA, 28 with OA) and 31 healthy controls. Clinical evaluations were also performed. RESULTS: In some RA sera, SHAP-HA complex levels were extremely high compared to control levels, but in OA sera no marked increase was observed compared to controls. This was also the case with the HA levels compared between RA and OA sera. However, in RA the levels of the SHAP-HA complex appear to be more related to clinical variables than are levels of HA, and the most significant correlations between levels of SHAP-HA complex and HA were found in the RA group. CONCLUSION: Quantitation of the SHAP-HA complex in sera may be useful as a joint marker that directly correlates to the degree of joint inflammation in RA, and offers new insight into the pathogenesis of arthritis. It may also serve as an independent criterion in the subsequent classification of RA and OA.

Ishiguro N, Ito T, Miyazaki K, Iwata H. · Department of Orthopaedic Surgery, Nagoya University School of Medicine, Japan. · J Rheumatol. · Pubmed #9918237 No free full text.

Abstract: OBJECTIVE: To investigate the correlation between synovial fluid (SF) concentrations of metalloproteinase (MMP) -2, -3, and -9, tissue inhibitors of metalloproteinases (TIMP)-1 and -2, chondroitin 4-, 6-sulfate (deltadi-C4S, deltadi-C6S), hyaluronic acid (deltadi-HA), antigenic keratan sulfate (KS), and radiologic grade in patients with rheumatoid arthritis (RA) and to assess the clinical value of these factors as disease markers. METHODS: Enzyme linked immunoassays and high performance liquid chromatography were used. SF samples were collected from 52 patients with RA. Radiographic (Larsen grade) and clinical evaluations were also done. RESULTS: There was no significant correlation between the concentrations of MMP, TIMP, and deltadi-C4S, deltadi-C6S, deltadi-HA, and antigenic KS. No significant correlations were found between the radiologic grade and the concentrations of MMP or TIMP in SF. There was a significant increase in the concentration of antigenic KS and deltadi-C6S/deltadi-C4S ratio in SF from patients with Larsen grade 2 compared to grade 5. A significant correlation between deltadi-C6S and antigenic KS concentrations in SF was observed. CONCLUSION: Although there were large variances between the samples in this study, proteoglycan metabolism in the cartilage matrix of the patients with RA might have been increased in the early phases of tissue destruction and decreased in advanced stages because of scanty cartilage tissue. The concentrations of MMP-2, -3, -9 and TIMP-1, -2 in SF did not seem to be influenced by the amount of residual cartilage.