Rheumatoid Arthritis: Takeuchi T

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.

Takeuchi T. · No affiliation provided · Nippon Naika Gakkai Zasshi. · Pubmed #19469079 No free full text.

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Takeuchi T. · Division of Rheumatology/Clinical Immunology, Saitama Medical Center, Saitama Medical University. · Nippon Rinsho. · Pubmed #19432131 No free full text.

Abstract: Given the recent consensus that main goal of therapy for rheumatoid arthritis (RA) is remission, it is extensively studied how to get remission effectively and early. Initial treatment with biologics along with methotrexate (MTX) has been shown to achieve clinical remission much greater than that with MTX alone, suggesting that early intervention with biologics plus MTX should be seriously considered. In this regard, personalized strategy to start biologics in individual patients based on the disease activity and prognosis factors has been proposed. In this review, indication and use of biologics in early RA are discussed by showing the clinical studies published in the literature.

Kameda H, Takeuchi T. · Department of Rheumatology/Clinical Immunology, Saitama Medical Center, Saitama Medical University. · Nippon Rinsho. · Pubmed #19280922 No free full text.

Abstract: Pathogenesis of rheumatoid arthritis is likely to implicate anti-citrullinated protein/ peptide antibody(ACPA) and an immunodistortion including abnormal T cell subpopulation. Based on above and other recent findings, new biological agents targeted to inflammatory cytokines such as tocilizumab, activated T cells (abatacept) or B cells (ocrelizumab), as well as new small molecule drugs such as JAK3 inhibitor, are sure to further facilitate remission without impaired activity of daily life in patients with RA. The contribution of Japanese physician-scientists to the progress in rheumatology has been significant as described in this review, and it must be increasingly greater in the near future.

Nagasawa H, Takeuchi T. · Department of Rheumatology and Clinical Immunology, Saitama Medical Center, Saitama Medical University. · Clin Calcium. · Pubmed #19252252 No free full text.

Abstract: Recently, the treatment of patients with rheumatoid arthritis has changed dramatically. The goal of therapy is not only the control of inflammation, but the prevention of joint destruction, the improvement and maintenance of good functional capacity, and moreover, complete remission or cure. Under the circumstance, tumor necrosis factor (TNF) -blocking agents, that have shown the excellent clinical effect and remarkable inhibition of joint destruction, are the medicine of important role.

Kameda H, Takeuchi T. · No affiliation provided · Nippon Naika Gakkai Zasshi. · Pubmed #18044154 No free full text.

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Takeuchi T. · Division of Rheumatology, Department of Internal Medicine, Saitama Medical Center, Saitama Medical University. · Nippon Rinsho. · Pubmed #17642230 No free full text.

Abstract: Biological agents targeting against a series of pro-inflammatory cytokines have provided an enormous impact on the therapeutic management on inflammatory disorders such as rheumatoid arthritis. Clinical development of biological agents in Japan, particularly, TNF inhibitors, has been reviewed in this paper, and future perspective is discussed.

Takeuchi T. · · Nippon Yakurigaku Zasshi. · Pubmed #17379969 No free full text.

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Takeuchi T. · No affiliation provided · Nippon Naika Gakkai Zasshi. · Pubmed #17037316 No free full text.

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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.

Takeuchi T. · Department of Rheumatology/Clinical Immunology, Saitama Medical Center. · Nippon Rinsho. · Pubmed #16164218 No free full text.

Abstract: Biological agents targeting on pro-inflammatory cytokines are developed, and provide a great impact on the medical management of rheumatoid arthritis (RA). Particularly, biologics against tumor necrosis factor(TNF) can not only induce great clinical improvement, but also halt structural damage on the joints. Now chimeric anti-TNFalpha monoclonal antibody, infliximab, full human anti-TNFalpha monoclonal antibody, adalimumab, and TNF receptor II (p75) -IgGFc fusion protein, etanercept, are widely used in the inflammatory disorders including RA. This review article shows the characteristics of these anti-TNF biologics on RA, and summarizes the efficacy as well as the safety of the agents.

Takeuchi T, Tsuzaka K, Kameda H, Amano K. · Second Department of Internal Medicine, Saitama Medical Center, Saitama Medical School, Kamoda 1981, Kawagoe, Saitama 350-8550, Japan. · Curr Drug Targets Inflamm Allergy. · Pubmed #16101536 No free full text.

Abstract: It is widely accepted that T cells with defective function play a central role in the pathogenesis of systemic lupus erythematosus (SLE). The detailed molecular mechanism underlying the aberrant function of SLE T cells is now being revealed. The TCR zeta chain, transcription factor, elf-1, inflammation signal transducer NF-kB, and PKC theta have been identified as the responsible molecules. In contrast to the defective signal transduction molecules, surface structures such as adhesion molecules, and co-stimulators have been reported to increase in their expression and function. Glucocorticoids and immunosuppressive agents have greatly improved the outcome of acute diseases and 5-year survival rate. However, it is suggested that long-term survival and quality of life appears to be unsatisfactory. Although the medical management of SLE is not sufficient to warrant long-term survival of young patients, recent progress in anti-cytokine biologics therapy against rheumatoid arthritis (RA) has facilitated searching for the molecular targets of SLE. In this report, we briefly review the molecular basis of SLE pathogenesis, and discuss possible therapeutic targets in this disease, focusing particularly on signal transduction and adhesion molecules in T cells.

Amano K, Takeuchi T. · Second Department of Internal Medicine, Saitama Medical Center, Saitama Medical School. · Nippon Rinsho. · Pubmed #15954438 No free full text.

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Nagasawa H, Takeuchi T. · Second Department of Internal Medicine, Saitama Medical Center, Saitama Medical School. · Nippon Rinsho. · Pubmed #15954362 No free full text.

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Kameda H, Takeuchi T. · Second Department of Internal Medicine, Saitama Medical Center. · Nippon Rinsho. · Pubmed #15954359 No free full text.

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Takeuchi T. · Second Department of Internal Medicine, Saitama Medical Center, Saitama Medical School. · Nippon Rinsho. · Pubmed #15799409 No free full text.

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Takeuchi T. · Second Department of Internal Medicine, Saitama Medical Center, Saitama Medical School. · Nippon Rinsho. · Pubmed #15799396 No free full text.

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Takeuchi T, Tsuzaka K, Abe T. · Second Department of Internal Medicine, Saitama Medical Center, Saitama Medical School, Kawagoe, Saitama, Japan. · Int Rev Immunol. · Pubmed #15204089 No free full text.

Abstract: SLE T cells may play a key role in autoantibody production in SLE B cells. In addition, accumulating evidence has shown that SLE T cells participate in the attack on target cells or tissues through the overproduction of pro-inflammatory cytokines or an increase in cell-to-cell adhesion. Thus, the functional abnormality of SLE T cells appears to be pivotal to an understanding of SLE pathogenesis. Accumulating evidence suggests that potential defects may reside in the proximal signal transduction around the TCR-CD3 complex. We have demonstrated that the expression of TCR zeta chain is significantly decreased in peripheral blood T cells from SLE patients. To explore the mechanism of defective expression of TCR zeta chain, we examined mRNA of TCR zeta, and found that two alternatively spliced variants such as exon 7 (-) and short 3'-UTR are detected in SLE. We review the possible role of the TCR zeta defects in autoimmunity and discuss how the splicing variants lead to downregulated protein expression of TCR zeta chain.

Takeuchi T, Amano K, Tsuzake K, Kameda H, Abe T. · No affiliation provided · Nippon Naika Gakkai Zasshi. · Pubmed #15052817 No free full text.

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Kameda H, Takeuchi T. · Second Department of Internal Medicine, Saitama Medical Center. · Nippon Rinsho. · Pubmed #12638224 No free full text.

Abstract: Patients with rheumatoid arthritis(RA) develop both generalized and periarticular osteoporosis. Both of them are believed to be associated with increased production of inflammatory cytokines(TNF alpha, IL-1 beta, IL-6) and increased formation and activation of osteoclasts. Whether glucocorticoids work positively or negatively on generalized/periarticular osteoporosis is still controversial. RANKL has been shown to be expressed on T cells and fibroblast-like cells in the synovium, thus 'RANKL-RANK' pathway is likely to play an important role in periarticular osteoporosis and bone erosion as well as generalized osteoporosis. Among various therapies for generalized/periarticular osteoporosis in RA, anti-cytokine antibodies/antagonists and osteoclast inhibitors including bisphosphonates are promising.

Takeuchi T, Amano K. · Second Department of Internal Medicine, Saitama Medical Center, Saitama Medical School. · Nippon Rinsho. · Pubmed #12510367 No free full text.

Abstract: Etanercept is a protein comprised of the extracellular domains of two TNF receptors attached to a Fc portion of an IgG. Etanercept was approved for not only reducing signs and symptoms but inhibiting of structural damage in patients with active RA who had an inadequate response to one or more DMARDs. Moreover, combination therapy with methotrexate will be attractive for severely active patients. The proportion of patients who have discontinued therapy due to adverse events is approximately 4%. Etanercept has not raised the risk for serious infections(0.04/patient-year) as well as malignancies. There are sporadic case reports of aplastic anemia, demyelination, lupus-like conditions, which are not significant so far. Etanercept may contribute rheumatologists to manage patients with RA.

Abe T, Takeuchi T. · 2nd Department of Internal Medicine, Saitama Medical Center/School, Japan. · Autoimmunity. · Pubmed #11905855 No free full text.

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Takeuchi T, Amano K. · No affiliation provided · Nippon Naika Gakkai Zasshi. · Pubmed #11215130 No free full text.

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Nishimoto N, Yoshizaki K, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Hashimoto J, Azuma J, Kishimoto T. · Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, Suita-City, Osaka, Japan. · Arthritis Rheum. · Pubmed #15188351 links to  free full text

Abstract: OBJECTIVE: Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates the immune response, inflammation, and hematopoiesis. Overproduction of IL-6 plays pathologic roles in rheumatoid arthritis (RA), and the blockade of IL-6 may be therapeutically effective for the disease. This study was undertaken to evaluate the safety and efficacy of a humanized anti-IL-6 receptor antibody, MRA, in patients with RA. METHODS: In a multicenter, double-blind, placebo-controlled trial, 164 patients with refractory RA were randomized to receive either MRA (4 mg/kg body weight or 8 mg/kg body weight) or placebo. MRA was administered intravenously every 4 weeks for a total of 3 months. The clinical responses were measured using the American College of Rheumatology (ACR) criteria. RESULTS: Treatment with MRA reduced disease activity in a dose-dependent manner. At 3 months, 78% of patients in the 8-mg group, 57% in the 4-mg group, and 11% in the placebo group achieved at least a 20% improvement in disease activity according to the ACR criteria (an ACR20 response) (P < 0.001 for 8-mg group versus placebo). Forty percent of patients in the 8-mg group and 1.9% in the placebo group achieved an ACR50 response (P < 0.001). The overall incidences of adverse events were 56%, 59%, and 51% in the placebo, 4-mg, and 8-mg groups, respectively, and the adverse events were not dose dependent. A blood cholesterol increase was observed in 44.0% of the patients. Liver function disorders and decreases in white blood cell counts were also observed, but these were mild and transient. There was no increase in antinuclear antibodies or anti-DNA antibodies. Anti-MRA antibodies were detected in 2 patients. CONCLUSION: Treatment with MRA was generally well tolerated and significantly reduced the disease activity of RA.

Hashimoto J, Garnero P, van der Heijde D, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Yoshikawa H, Nishimoto N. · Osaka University Graduate School of Medicine, Osaka, Japan. · Mod Rheumatol. · Pubmed #19452245 No free full text.

Abstract: The aim of this study was to evaluate the predictive value of biological, radiological and clinical parameters for the progression of radiographic joint damage in rheumatoid arthritis (RA) patients treated with conventional disease-modifying anti-rheumatic drugs (DMARDs). We analyzed the 145 patients with active RA for less than 5 years who were participating in the prospective 1-year randomized controlled trial of tocilizumab (SAMURAI trial) as a control arm treated with conventional DMARDs. Progression of joint damage was assessed by sequential radiographs read by two independent blinded X-ray readers and scored for bone erosion and joint space narrowing (JSN) using the van der Heijde-modified Sharp method. Multivariate analysis revealed that increased urinary levels of C-terminal crosslinked telopeptide of type II collagen (U-CTX-II), an increased urinary total pyridinoline/total deoxypyridinoline (U-PYD/DPD) ratio and low body mass index (BMI) at baseline were independently associated with a higher risk for progression of bone erosion. In addition to these three variables, the JSN score at baseline was also significantly associated with an increased risk of progression of the JSN score and total Sharp score. High baseline U-CTX-II levels, U-PYD/DPD ratio and JSN score and a low BMI are independent predictive markers for the radiographically evident joint damage in patients with RA treated with conventional DMARDs.