Rheumatoid Arthritis: Eguchi K

Koike R, Takeuchi T, Eguchi K, Miyasaka N, Anonymous00064. · Department of Pharmacovigilance, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. · Mod Rheumatol. · Pubmed #18084695 No free full text.

Abstract: Application of biological agents targeting tumor necrosis factor-alpha (TNF-alpha) caused a paradigm shift in the treatment of rheumatoid arthritis (RA). The introduction of infliximab in 2003 and etanercept in 2005 in Japan had a significant impact on both Japanese rheumatologists and RA patients, although serious adverse effects such as bacterial pneumonia, tuberculosis and Pneumocystis jiroveci pneumonia are significant concerns. Based on the data from post-marketing surveillance in Japan and accumulating evidence worldwide, the Internal Medicine Rheumatology Study Group of the Ministry of Health, Labor and Welfare (MHLW), Japan, has updated the guidelines for the use of anti-TNF-alpha agents for RA, which were subsequently approved by the Board of Japan College of Rheumatology (JCR). In the present revised guidelines, we combined the guidelines for use of each of infliximab and etanercept together with some modifications and precautions, paying special attention to serious adverse reactions. Although it is still controversial whether the use of TNF-alpha blocking agents per se increases the risk of infection or not, bacterial pneumonia, regardless of the pathogens, is the most frequent complications in RA. The risk factors associated with pneumonia identified in the post-marketing surveillance of infliximab in Japan are presented in this guideline. The diagnostic algorithm is also designed for early diagnosis and treatment of pulmonary lesions seen during the treatment of biological agents. Preventive measures and precautions against tuberculosis, another frequent and significant complication in Japan, are also described. Furthermore, risk factors for developing Pneumocystis pneumonia, which uniquely occurs at 30- to 50-fold frequency under TNF-alpha blockade therapy in Japan, are described here and its preventive measures are discussed. It is stressed that secondary-care rheumatologists should be better familiarized with the proper use of TNF-alpha blocking agents and be alert to any adverse events for a better management of RA patients.

Fujikawa K, Kawakami A, Eguchi K. · Unit of Translational Medicine, Department of Immunology and Rheumatology, Graduate School of Biomedical Sciences, Nagasaki University. · Nippon Rinsho. · Pubmed #17642234 No free full text.

Abstract: TNF is a central cytokine in the pathogenesis of rheumatoid arthritis(RA), which induces synovitis as well as joint damage. Etanercept is a recombinant human soluble TNF receptor that binds specifically to TNF receptor, and inhibits TNF receptor-mediated signaling cascade. Recent investigations have revealed successful clinical efficacy of biologics in RA including etanercept. We reviewed here the structure and efficacy of etanercept in RA according to the published evidence.

Eguchi K. · Nagasaki University, Graduate School of Biomedical Sciences, First Department of Internal Medicine. · Clin Calcium. · Pubmed #17404480 No free full text.

Abstract: It is proposed by hypothesis that early intervention in rheumatoid arthritis might result in remission or cure. It was undertaken to classify rheumatoid arthritis (RA) in early stage from undifferentiated arthritis (UA) and predict the progression of joint destruction at the first visit using by serological markers and magnetic resonance imaging (MRI) . Logistic regression analysis using the statistical analysis system software demonstrated that the presence of anti-cyclic citrullinated peptide (CCP) antibody and/or immunoglobulin M-rheumatoid factor (IgM-RF) , symmetric synovitis and bone marrow edema and/or bone erosion at entry could discriminate patients with RA from UA or other than RA. A total score of two or more of the three objective measures allowed the prediction for RA with 83% sensitivity and 85% specificity, respectively. The presence of bone marrow edema and/or bone erosion determined by MRI is a forerunner of bone erosion on plain radiography. Both presences of anti-CCP antibody and/or IgM-RF and bone marrow edema determined by MRI may predict the early-stage of RA and the progression of articular destruction. From the above findings, it was recommended that early intervention of anti-rheumatic drugs and/or TNF blocker should be started the UA patients with both autoantibody (anti-CCP antibody and/or IgM-RF) and bone marrow edema determined by MRI.

Kawakami A, Tamai M, Eguchi K. · First Department of Internal Medicine, Graduate School of Biomedical Sciences, Nagasaki University. · Nihon Rinsho Meneki Gakkai Kaishi. · Pubmed #17332703 links to  free full text

Abstract: Recent clinical studies of rheumatoid arthritis reveal that therapeutic intervention early in rheumatoid arthritis leads to less joint damage, indicating the importance of early diagnosis of RA for improvement of prognosis. According to the data of our "Early Arthritis Prospective Cohort", we have found that early arthritis patients, described as undifferentiated arthritis, progress to rheumatoid arthritis at high frequency if the patients positive with anti-cyclic citrullinated peptide antibody (anti-CCP antibody) and bone marrow edema at the entry. In addition, we are going to classify the pathologic status (disease severity) of early arthritis patients by serologic variables, radiographic findings and genetic analysis.

Nakamura H, Kawakami A, Eguchi K. · The First Department of Internal Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki City, Nagasaki, Japan. · Transl Res. · Pubmed #17162248 No free full text.

Abstract: The major target organs of Sjögren's syndrome (SS) are lacrimal glands and salivary glands where prominent lymphocytic infiltration occurs, which may induce varying levels of autoantibody production. Multiple factors, including environmental stress, viral infection, hormonal imbalance, and apoptosis, are thought to be involved in the pathogenesis of SS. Production of anti-SS-A/Ro and anti-SS-B/La antibodies is thought to be regulated by the presentation of autoantigens in context with an aberrant expression pattern of human leukocyte antigen (HLA) in situ. Molecular mimicry with some viral sequences is also hypothesized. The apoptosis-resistance phenotype of B cells in labial salivary glands (LSGs) of SS is important in autoantibody production. CD40/CD40L (CD40 ligand) and Bcl-2 family proteins, in tandem with B cell-activating factor (BAFF), are supposed to protect infiltrating lymphocytes from apoptosis. Anti-muscarinic3 receptor antibody plays an important role in cholinergic hyperresponsiveness in SS. Fragmentation of autoantigens such as SS-B/La or alfa-fodrin during the process of apoptosis causes the redistribution of these autoantigens, leading to the production of autoantibodies in SS. In this review, the role of autoantibodies found in SS, corresponding to clinical aspects of each antibody as well as the mechanisms of production, is discussed.

Miyasaka N, Takeuchi T, Eguchi K. · Department of Medicine and Rheumatology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. · Mod Rheumatol. · Pubmed #16633923 No free full text.

Abstract: Application of biological agents targeting inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) dramatically caused a paradigm shift in the treatment of rheumatoid arthritis (RA). Infliximab, a chimeric anti-TNF-alpha monoclonal antibody, has initially been introduced to Japan in 2003 and shown to be dramatically effective in alleviating arthritis refractory to conventional treatment. However, serious adverse events such as bacterial pneumonia, tuberculosis, and Pneumocystis jiroveci pneumonia were reported to be in relatively high incidence; i.e., 2%, 0.3%, and 0.4%, respectively, in a strict postmarketing surveillance of an initial 4000 cases in Japan. Etancercept, a recombinant chimeric protein consisting of p75 TNF-alpha receptor and human IgG, was subsequently introduced to Japan in March of 2005. We therefore drew up treatment guidelines for the use of etanercept to avoid potential serous adverse events, since only approximately 150 cases have been included in the clinical study of etanercept in Japan. The guidelines were initially designed by the principal investigators (N.M, T.T., K.E.) of rheumatoid arthritis study groups of the Ministry of Health, Labor and Welfare (MHLW), Japan, and finally approved by the board of directors of the Japan College of Rheumatology. The MHLW assigned a duty to the pharmaceutical companies to perform a complete postmarketing surveillance of an initial 3000 cases to explore any adverse events, and this was performed according to the treatment guidelines shown in this article.

Ueki Y, Eguchi K. · Rheumatic and Collagen Disease Center, Sasebo Chuo Hospital. · Nippon Rinsho. · Pubmed #15799436 No free full text.

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Eguchi K. · First Department of Internal Medicine, Graduate School of Biomedical Sciences, Nagasaki University. · Nippon Rinsho. · Pubmed #15799412 No free full text.

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Origuchi T, Eguchi K. · Nagasaki University School of Health Sciences. · Nippon Rinsho. · Pubmed #15799346 No free full text.

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Kawakami A, Tanaka F, Tamai M, Nakamura H, Eguchi K. · First Department of Internal Medicine, Graduate School of Biomedical Sciences, Nagasaki University. · Nippon Rinsho. · Pubmed #15799326 No free full text.

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Ueki Y, Takashima H, Matsumoto K, Miyake S, Hidaka T, Suzuki K, Eguchi K. · Rheumatic and Collagen Disease Center, Sasebo Chuo Hospital. · Nippon Rinsho. · Pubmed #12510353 No free full text.

Abstract: Filtration Leukocytapheresis(LCAP) is an alternative to thoracic duct drainage and LCAP using a centrifuge method with the advantages that it can be performed easily and inexpensively. Clinical trials revealed that LCAP is a safe and effective therapy for patients with drug-resistant rheumatoid arthritis(RA). Assessment of RA before and after LCAP showed a substantial and rapid improvement in tender joints counts, swollen joint counts, and patient's and physician's assessments. Careful analysis indicated that 64-80% of patients with RA showed > or = 20% improvement following LCAP therapy. Furthermore, we investigated the clinical evaluation of LCAP for RA over the 3 year-study period. Possible therapeutic mechanisms of LCAP on RA are summarized.

Kawakami A, Eguchi K. · The First Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. · Med Electron Microsc. · Pubmed #12111401 No free full text.

Abstract: A low rate of as well as a high rate of apoptotic cell death is involved in the development of various human autoimmune diseases. In rheumatoid arthritis (RA), impaired apoptosis of rheumatoid synovial cells appears to induce hyperplasia of the synovial tissues, whereas the acceleration of apoptotic cell death of osteoblasts may contribute to periarticular bone loss in patients with RA. Humoral factors including cytokines and growth factors present in the rheumatoid synovial tissues modulate the expression of apoptosis-related molecules in the cells, which inhibits or stimulates the apoptotic process of synovial cells and osteoblasts. In addition, investigations of animal arthritis models suggest that an enforced induction of apoptotic cell death of synovial cells ameliorates synovial tissue hyperplasia. The increase of salivary gland cell apoptosis and the resistance of apoptotic cell death in salivary infiltrating mononuclear cells have been observed in patients with Sjögren's syndrome (SS). Immunohistochemical studies indicate that X chromosome linked inhibitor of apoptosis protein in salivary gland cells as well as Bcl-2/Bcl-xL in salivary infiltrating mononuclear cells may be critical anti-apoptogenic molecules in each cell type. Human T-lymphotropic virus type I (HTL V-I) is one of the pathogenic organisms for RA and SS, and we demonstrated that HTL V-I tax stimulates NF-kappa B nuclear translocation, inhibiting apoptotic cell death of human host cells, which may accelerate the autoimmune process. The association between the apoptosis of thyrocytes and the process of autoimmune thyroid diseases has also been examined, and our data suggest that Fas-mediated apoptosis of human thyrocytes is modulated by thyroid-stimulating antibodies, thyroid stimulation blocking antibodies, and cytokines. These data indicate that the correction of apoptotic cell death in each cell type will become a new therapeutic strategy for treatment of human autoimmune diseases.

Eguchi K. · First Department of Internal Medicine, Nagasaki University School of Medicine. · Intern Med. · Pubmed #11334384 links to  free full text

Abstract: Over the past decade, our understanding of apoptosis, or programmed cell death, has increased greatly, with the identification of some of the major components of the apoptotic program and the processes regulating their activation. Although apoptosis is an intrinsic process present in all cells, it can be regulated by extrinsic factors, including growth factors, cell surface receptors, cellular stress and hormones. Apoptotis plays an important role in autoimmune diseases. Normal thyrocytes could induce apoptosis of infiltrating activated T cells and protect against attack by such cells, i.e., the normal thyroid tissues act as an immune privileged site. In Hashimoto's thyroiditis (HT), Fas-mediated apoptosis of thyrocytes in a section of tissues is due to at least two separate mechanisms, the first by infiltrating activated T cells, and the other by FasL-positive thyrocytes in a suicidal or fratricidal fashion. A common feature of autoimmune diseases such as systemic lupus erythematosus (SLE) is the breakdown of tolerance of self antigens, a consequence of which is the production of autoantibodies reactive with multiple self proteins. Evidence is accumulating that modifications of autoantigens during apoptosis lead to the development of autoantibodies by bypassing the normal mechanisms of tolerance. Tissue homeostasis is maintained through a balance between cell proliferation and apoptotic cell death. Rheumatoid arthritis (RA) is characterized by pronounced hyperplasia of the synovial tissue, cell infiltration and periarticular osteoporosis. Enhanced Bcl-2 expression and NF-kappaB nuclear translocation of synovial cells are induced by inflammatory cytokines and/or growth factors. These synovial cells become resistant toward apoptosis triggered by various stimuli. The infiltrated cells which are defect in activation-induced cell death can cause autoimmunity by allowing the survival of autoreactive T and B cells. These data suggest that apoptosis might be implicated with the pathogenesis of autoimmunity, whereas the mechanisms might be distinct in each autoimmune disease.

Eguchi K. · No affiliation provided · Nippon Naika Gakkai Zasshi. · Pubmed #11215129 No free full text.

This publication has no abstract.

Eguchi K, Saito K, Kondo M, Hidaka T, Ueki Y, Tanaka Y, Anonymous00065. · First Department of Internal Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan. · Mod Rheumatol. · Pubmed #18084700 No free full text.

Abstract: To evaluate the efficacy of high-dose leukocytapheresis (LCAP) using a large filter in patients with refractory rheumatoid arthritis (RA), we conducted a multicenter, nonrandomized, open-label clinical study. Thirty patients with highly active RA were treated with high-dose LCAP performed 3-5 sessions at 1-week intervals using a CS-180S filter (CS-180S group); the treatment involves the removal of leukocytes from a higher blood volume per body weight (100;Sml/kg). The clinical response was evaluated at 4 and 8 weeks after a series of LCAP using the 28-joint disease activity score (DAS28). Similar data of 53 patients treated with conventional LCAP (60;Sml/kg) using a standard filter, CS-100, were compared as a control (CS-100 group). The CS-180S filter demonstrated a higher adsorption capacity for leukocytes, particularly lymphocytes. The CS-180S group exhibited significant improvements in each item of DAS28 after treatment although the CS-100 group did not demonstrate such improvements in the CRP level and the ESR. Compared to the CS-100 group, the patients of the CS-180S group exhibited a tendency toward improvement with respect to the CRP level and ESR (P = 0.057 and 0.041, respectively). According to the EULAR improvement criteria based on DAS28, 60% and 45% of the patients from CS-180S and CS-100 groups achieved moderate or more responses, respectively, at 4 weeks after treatment. These results suggest that compared to conventional LCAP, high-dose LCAP may enhance the suppression of RA disease activity.

Nakamura H, Ueki Y, Sakito S, Matsumoto K, Yano M, Miyake S, Tominaga Y, Eguchi K. · Department of Internal Medicine, Sasebo Chuo Hospital, Japan. · Clin Exp Rheumatol. · Pubmed #10949718 No free full text.

Abstract: OBJECTIVE: We previously reported the presence of high serum concentrations of nitric oxide (NO) in patients with rheumatoid arthritis (RA). In this study we evaluated the effect of actarit on patients with early and advanced stages of RA and the relationship between RA activity and serum NO levels. METHODS: Thirty-seven RA patients who were undergoing care at Sasebo Chuo Hospital were entered into the study. Patients were divided into two groups based on the severity of their disease: group I (stages I and II) and group II (stages III and IV). NO concentrations in serum samples were measured by the chemiluminescence method. RESULTS: Morning stiffness, the number of tender and swollen joints, grip strength, pain score, modified Health Assessment Questionnaire score (mHAQ), ESR, CRP and the Lansbury index significantly improved during 24 weeks of treatment in group I. Patients in group II did not show improvement in morning stiffness, pain score, ESR or CRP during treatment. The concentrations of NO in group I were significantly reduced at 8 weeks after administration of actarit. Those in group II showed a delayed response; a significant decrease in NO occurred at 20 weeks. The improvement in the number of tender and swollen joints, grip strength, pain score, mHAQ and Lansbury index noted in group I preceded the fall in NO concentrations. CONCLUSION: Our results demonstrate that actarit improves disease activity in early phase RA by suppressing serum NO levels. The results suggest that NO is a useful marker for monitoring improvement in the early stages of RA.

Ueki Y, Yamasaki S, Kanamoto Y, Kawazu T, Yano M, Matsumoto K, Miyake S, Tominaga Y, Iwamoto U, Suemitsu J, Matsuno Y, Sizume Y, Takenaka Y, Eguchi K. · Department of Internal Medicine, Sasebo Chuo Hospital, Sasebo, Asahi Medical Research and Development Laboratory, Oita, Asahi Medical Technical Department, Tokyo, Japan. · Rheumatology (Oxford). · Pubmed #10725066 links to  free full text

Abstract: OBJECTIVES: To evaluate the efficacy of filtration leucocytapheresis (LCP) for rheumatoid arthritis (RA). METHODS: LCP was carried out three times, with 1 week separating each session, in 25 drug-resistant RA patients. RESULTS: During each session, 96, 98, 61, 84 and 8% of the granulocytes, monocytes, lymphocytes, platelets and erythrocytes, respectively, that entered the LCP filter were removed. The number of granulocytes, monocytes and lymphocytes in the peripheral blood significantly decreased during each session of LCP. However, there was no significant decrease in the number of circulating blood cells during the study period. On average, 110 x 10(8) granulocytes, 5.23 x 10(8) monocytes, and 20.5 x 10(8) lymphocytes were removed during LCP therapy. Assessment of RA before and after LCP showed a substantial and rapid improvement in the tender joints counts, swollen joint counts, and patient's and physician's assessments. No adverse reactions or complications were noted. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels decreased following LCP, although the change in the latter parameter was statistically insignificant. The concentrations of serum albumin, gamma-globulin, IgG, IgM, CH50 and rheumatoid factor titres did not change during or after LCP. Careful analysis indicated that 16 of 25 patients with RA showed > or =20% improvement following LCP therapy. CONCLUSIONS: Our results suggest that filtration LCP to remove leucocytes from the peripheral blood exerts an immunomodulatory effect in patients with RA.

Tamai M, Kawakami A, Uetani M, Takao S, Arima K, Iwamoto N, Fujikawa K, Aramaki T, Kawashiri SY, Ichinose K, Kamachi M, Nakamura H, Origuchi T, Ida H, Aoyagi K, Eguchi K. · Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. · Arthritis Rheum. · Pubmed #19479686 No free full text.

Abstract: OBJECTIVE: To evaluate whether magnetic resonance imaging (MRI) of the wrists and finger joints and an analysis of serologic autoantibodies are clinically meaningful for the subsequent development of rheumatoid arthritis (RA) in patients with undifferentiated arthritis (UA). METHODS: A total of 129 patients with UA, a disease status formally confirmed by a rheumatologist over a period of at least 1 year, were included. Gadolinium-diethylenetriamine-enhanced MRI of both wrists and finger joints and serologic variables were examined upon admission to our Early Arthritis Clinic at Nagasaki University. After a prospective followup of 1 year, a predictive value for the development of RA was determined for each patient. RESULTS: The subjects were evaluated for their positive or negative status with respect to 3 objective measures at study entry: anti-cyclic citrullinated peptide (anti-CCP) antibodies and/or IgM-rheumatoid factor, MRI-proven symmetric synovitis, and MRI-proven bone edema and/or bone erosion. The patients who were positive for at least 2 of these measures progressed to RA at 1 year with a 79.7% positive predictive value (PPV), 63.0% negative predictive value, 75.9% specificity, 68.0% sensitivity, and 71.3% accuracy. Furthermore, in 22 UA patients positive for both anti-CCP antibodies and MRI-proven bone edema who were considered to have progressed to RA at 1 year, the PPV was increased to 100%. A close correlation was found between the present rule and that established in the Leiden Early Arthritis Cohort. CONCLUSION: MRI-proven early joint damage in conjunction with serologic autoantibodies is efficient in predicting progression from UA to RA. This method can be used to identify patients who would benefit from early treatment with disease-modifying antirheumatic drugs.

Fujikawa K, Kawakami A, Tamai M, Uetani M, Takao S, Arima K, Iwamoto N, Aramaki T, Kawashiri S, Ichinose K, Kamachi M, Nakamura H, Origuchi T, Ida H, Aoyagi K, Eguchi K. · Unit of Translational Medicine, Department of Immunology and Rheumatology, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. · J Rheumatol. · Pubmed #19447929 No free full text.

Abstract: OBJECTIVE: To identify the significance of serum cartilage oligomeric matrix protein (COMP), a marker of cartilage turnover, in patients with early-stage rheumatoid arthritis (RA) in relation to other serologic variables and magnetic resonance imaging (MRI) features. METHODS: Ninety-eight patients with early-stage RA, whose disease duration from onset was less than 2 years, were enrolled. The objective measures at baseline were Disease Activity Score (DAS28), serum C-reactive protein (CRP), serum matrix metalloproteinase-3 (MMP-3), serum antibodies against cyclic citrullinated peptide (anti-CCP), and MRI features of both wrist and finger joints. The MRI features included the number of sites scored positive for synovitis, bone edema, and bone erosion. RESULTS: Serum COMP concentration was not different among groups identified with low, moderate, and high DAS28-CRP values. However, COMP values were statistically high in subjects positive for bone erosions on MRI compared with the subjects who were negative for bone erosions. A positive correlation of COMP with CRP and with MMP-3 values was also identified. CONCLUSION: Elevation of COMP may reflect joint damage that is dependent on the synovial inflammatory process in early-stage RA.

Aramaki T, Ida H, Izumi Y, Fujikawa K, Huang M, Arima K, Tamai M, Kamachi M, Nakamura H, Kawakami A, Origuchi T, Matsuoka N, Eguchi K. · First Department of Internal Medicine, Nagasaki University Hospital of Medicine and Dentistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan. · Mod Rheumatol. · Pubmed #19283441 No free full text.

Abstract: To elucidate the characterization of peripheral natural killer (NK) cells in patients with rheumatoid arthritis (RA), we investigated the NK cell activity, the expression of NK cell activating receptors and intracellular molecules. The NK activity was analyzed in 27 RA patients, 22 primary Sjögren's syndrome (SS) patients, and 15 healthy individuals using the (51)Chrominium release assay. The expression of NK cell activating receptors (NKG2D, CD244, CD2, and CD16) and intracellular molecules (granzyme B, perforin, and TCR zeta chain) in CD3-CD56+ cells were characterized by flow cytometry. The serum cytokine levels (IL-6, TNFalpha, and IL-18) were measured using ELISA. Both the NK cell activity and the activity on a per-cell basis were observed to significantly decrease in the RA patients in comparison to the controls. The expression of NKG2D and CD244 also significantly decreased in both the RA and primary SS patients, whereas the significant decrease in the CD16 expression was only observed in the RA patients. The titer of the serum IL-6, TNFalpha, and IL-18 was significantly higher in the RA patients than in the controls. These data suggest that a low NK activity on a per-cell basis might therefore contribute to an impaired NK activity in the patients with RA.

Migita K, Nakamura T, Maeda Y, Miyashita T, Koga T, Tanaka M, Nakamura M, Komori A, Ishibashi H, Origuchi T, Ida H, Kawasaki E, Yasunami M, Eguchi K. · Clinical Research Center, NHO Nagasaki Medical Center Omura, Japan. · Clin Exp Rheumatol. · Pubmed #19210876 No free full text.

Abstract: OBJECTIVE:Familiar Mediterranean Fever (FMF) is common among Mediterranean populations, while other populations are rarely affected. The aim of this study was to assess the involvement of MEFV gene mutations among Japanese rheumatoid arthritis patients with or without amyloid A (AA) amyloidosis. METHODS:The frequency of the MEFV mutations, which were identified in Japanese FMF patients, was determined in 126 Japanese RA patients and 76 Japanese healthy subjects.RESULTS:The M694I mutation was not observed among RA patients and healthy subjects. Allele frequency of R408Q, P369S, E148Q, L110P mutations account respectively for 3.3%, 3.9%, 23.7%, 9.2% in healthy subjects and 5.6%, 6.7%, 24.2%, 9.5% in RA patients. The overall mutation rate was comparable between the RA patients and healthy subjects, as well as between the RA patients with and without amyloidosis.CONCLUSION:This study shows the high prevalence of mutations of the MEFV genes in Japanese RA patients. However, our data suggest that the MEFV gene mutations may not be a genetic factor affecting the susceptibility of RA or the development of amyloidosis in a Japanese population.

Iwamoto N, Kawakami A, Tamai M, Fujikawa K, Arima K, Aramaki T, Kawashiri S, Ichinose K, Kamachi M, Nakamura H, Origuchi T, Ida H, Eguchi K. · Unit of Translational Medicine, Department of Immunology and Rheumatology, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. · J Rheumatol. · Pubmed #19132785 No free full text.

Abstract: OBJECTIVE: To investigate whether anticyclic citrullinated peptide antibodies (anti-CCP) predict the subset of Japanese patients with Sjögren's syndrome (SS) with articular manifestations. METHODS: Eighty-seven patients with SS were enrolled. Prevalence of anti-CCP antibodies, IgM rheumatoid factor, anti-Ro/SSA antibody, anti-La/SSB antibody, and serum IgG concentration and their relation to articular manifestations were examined. Articular manifestations included morning stiffness and the presence of tender or swollen joints. RESULTS: Eighty-seven SS patients were divided into 3 groups: 14 secondary SS with nonerosive rheumatoid arthritis (RA); 47 primary SS with articular manifestations; and 26 primary SS without articular manifestations. Ten out of 14 secondary SS with nonerosive RA expressed anti-CCP. Anti-CCP was the only statistically proven marker preferentially distributed in patients with articular manifestations (the first 2 groups) compared to primary SS without such manifestations; however, its frequency was low in primary SS. No patient with primary SS without articular manifestations expressed anti-CCP. CONCLUSION: Anti-CCP is found in the subset of Japanese with SS with articular manifestations although most of those with anti-CCP-positive SS were classified as secondary SS with RA.

Nakamura H, Usa T, Motomura M, Ichikawa T, Nakao K, Kawasaki E, Tanaka M, Ishikawa K, Eguchi K. · The First Department of Internal Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki City, Nagasaki, Japan. · J Endocrinol Invest. · Pubmed #19092289 No free full text.

Abstract: OBJECTIVE: We determined the autoantibody profile in autoimmune thyroid diseases (AITD) and examined the distribution of thyroid-related autoantibodies in other autoimmune disorders. METHODS: We tested sera from 234 patients with Graves' disease (GD), 130 with Hashimoto's thyroiditis (HT), 249 with other autoimmune diseases, and 50 healthy controls by enzyme-linked immunosorbent assay or radioimmunoassay. RESULTS: Autoantibodies except TSH receptor antibody (Ab), anti-thyroglobulin (Tg) Ab and anti-thyroid peroxidase (TPO) Ab were not significantly prevalent in patients with AITD despite a significantly high elevation of thyroid-related Ab. Significant prevalence of autoantibodies related to AITD was observed in type 1 diabetes patients. Elevation of anti-Tg Ab was seen in patients with primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH), and anti-TPO Ab was elevated in patients with PBC. Although the prevalence of anti-acetylcholine receptor Ab and systemic lupus erythematosus (SLE)- related Ab was significant in AIH, primary Sjögren's syndrome (pSS)-related Ab were also found in both liver diseases. In myasthenia gravis (MG) patients, thyroid-related Ab and pSS-related Ab were detected in both MG groups, although SLE-related Ab were limited to the anti-muscle specific kinase Ab-positive MG patients. In patients with connective tissue diseases, anti- Tg Ab and anti-TPO Ab were significantly prevalent. CONCLUSION: Thyroid-related Ab were significantly elevated in all autoimmune diseases. Conversely, the elevations of Ab were not significant in the patients with AITD, suggesting a close relationship between AITD and other immune-mediated diseases.

Nakamura H, Takagi Y, Kawakami A, Ida H, Nakamura T, Nakamura T, Eguchi K. · The First Department of Internal Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Japan. · Clin Exp Rheumatol. · Pubmed #18799099 No free full text.

Abstract: OBJECTIVE: The role of HTLV-I infection in Sjögren's syndrome (SS) remains unclear. In this study, we clinically compared radiographic imaging with histological cellular infiltration between HTLV-I-seropositive and HTLV-I-sero-negative SS. METHODS: Sixty primary SS patients were divided into two age-matched groups based on the seropositivity of the anti-HTLV-I antibody. We evaluated the two groups through labial salivary gland biopsy-proven cellular infiltration and sialography-proven radiographic gland destruction. RESULTS: In these 60 pSS patients, the incidence of abnormalities as determined by salivary gland biopsy and sialography was 51.7% (31/60) and 76.7% (46/60), respectively. Although there was no difference in the prevalence of abnormal findings between salivary gland biopsy and sialography in the whole 60 patients, there were significantly fewer abnormalities determined by sialography in HTLV-I-seropositive SS patients in comparison with HTLV-I-seronegative SS patients. Also, these findings were strengthened by the results that none of HTLV-I-seropositive SS patients with focus score 0 had abnormal sialography findings. CONCLUSION: Our results suggest that HTLV-I infection results in resistance toward salivary gland destruction of Sjögren's syndrome.

Nakamura H, Kawakami A, Iwamoto N, Ida H, Koji T, Eguchi K. · Department of Immunology and Rheumatology, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. · Apoptosis. · Pubmed #18791828 No free full text.

Abstract: Expressions of the effector molecules of Fas-mediated apoptosis in primary cultured salivary gland epithelial cells (SGEC) of primary Sjögren's syndrome (pSS) remain to be clarified. We focused on Fas-mediated caspase cleavage compared to tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis. Induction of apoptosis was performed by anti-Fas antibody coupled with PI3K inhibitor, or TRAIL. Activation of caspases, cytochrome C, and apoptotic protease activating factor-1 (Apaf-1) was determined by western blotting or immunofluorescence observed by confocal microscopy. Fas-mediated apoptosis and activation of caspase 3/8 were induced in the presence of LY294002. TRAIL-induced apoptosis in SGEC, which was stronger than that induced by anti-Fas antibody. TRAIL-induced caspase 9 cleavage accompanied by activation of cytochrome C and Apaf-1 were not mediated by anti-Fas antibody. Our results suggest that death receptor-dependent apoptosis in primary cultured SGEC is regulated by the engagement of type II cells in pSS.