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Rheumatoid Arthritis: HELP
Articles by Yoshiya Tanaka
Based on 252 articles published since 2009
(Why 252 articles?)
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Between 2009 and 2019, Yoshiya Tanaka wrote the following 252 articles about Arthritis, Rheumatoid.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6 · 7 · 8 · 9 · 10 · 11
1 Editorial IL-6 targeting compared to TNF targeting in rheumatoid arthritis: studies of olokizumab, sarilumab and sirukumab. 2014

Tanaka, Yoshiya / Martin Mola, Emilio. ·The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan. · Servicio de Reumatología, Hospital Universitario La Paz, Universidad Autónoma de Madrid, Paseo de la Castellana 261, Madrid, Spain. ·Ann Rheum Dis · Pubmed #24833786.

ABSTRACT: -- No abstract --

2 Review Clinical immunity in bone and joints. 2019

Tanaka, Yoshiya. ·The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Kitakyushu, 807-8555, Japan. tanaka@med.uoeh-u.ac.jp. ·J Bone Miner Metab · Pubmed #30324535.

ABSTRACT: The immune system and bone metabolism influence each other. An imbalance in the immune system, resulting in inflammatory stimuli may induce an imbalance in bone turnover via induction of osteoclast differentiation and inhibition of osteoblast differentiation, leading to various pathological conditions including osteoporosis. T-cell subsets, helper T (Th)1 and Th17, which activate the immune system, induce osteoclasts, whereas regulatory T (Treg) cells, responsible for immunosuppression, inhibit osteoclastic differentiation. In addition, inflammatory cytokines, such as the tumor necrosis factor (TNF), also cause an imbalance in bone turnover, induction of osteoclasts and inhibition of osteoblasts. Treatments targeting the immune system may regulate abnormalities in bone metabolism, while also controlling immune abnormalities. In rheumatoid arthritis (RA), a representative autoimmune disease, immune abnormality and accompanying prolongation of synovial inflammation cause bone and cartilage destruction, periarticular osteoporosis, and systemic osteoporosis. Joint damage and osteoporosis in RA occur through totally different mechanisms. Stimulation by inflammatory cytokines induces the expression of the receptor activator for nuclear factor-κB ligand (RANKL) in T cells and synovial cells, thereby inducing bone destruction due to osteoblast-independent osteoclast maturation. However, biological products targeting TNF or interleukin-6 not only control disease activity, but also inhibit joint destruction. However, these biological products are not effective for osteoporosis. Conversely, anti-RANKL antibody inhibits osteoporosis and bone destruction, but exerts no influence on RA disease activity. Such differences in therapeutic efficacy may indicate the necessity for rethinking current theories on the mechanism of bone metabolism abnormality and joint destruction. Understanding the mechanisms underlying these pathologies via commonalities existing between the immune system and the metabolic system may lead to the development of new treatments.

3 Review Mechanisms and therapeutic targets for bone damage in rheumatoid arthritis, in particular the RANK-RANKL system. 2018

Tanaka, Yoshiya / Ohira, Takeshi. ·The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahata-nishi, Kitakyushu 807-8555, Japan. Electronic address: tanaka@med.uoeh-u.ac.jp. · Clinical Development Department, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. ·Curr Opin Pharmacol · Pubmed #29702364.

ABSTRACT: Rheumatoid arthritis (RA), a chronic inflammatory disorder, causes swelling, bone erosion, and joint deformity. Bone erosion in RA-affected joints arises from activation of osteoclasts by inflammatory processes. RA patients may also have primary, disease-related, or glucocorticoid-induced osteoporosis, caused by a disrupted balance between osteoclasts and osteoblasts. Disease-modifying antirheumatic drugs (DMARDs) interfere with the processes causing inflammation in the joint but do not sufficiently treat bone erosion and osteoporosis. Denosumab, an inhibitor of receptor activator of nuclear factor κ-B ligand (RANKL), protects bones in osteoporosis patients. Clinical studies have demonstrated that denosumab can also prevent bone erosion in RA patients. Because joint destruction progresses in some patients treated with DMARDs alone, denosumab will likely become standard treatment for some RA patients.

4 Review Clinical practice guideline for Sjögren's syndrome 2017. 2018

Sumida, Takayuki / Azuma, Naoto / Moriyama, Masafumi / Takahashi, Hiroyuki / Asashima, Hiromitsu / Honda, Fumika / Abe, Saori / Ono, Yuko / Hirota, Tomoya / Hirata, Shintaro / Tanaka, Yoshiya / Shimizu, Toshimasa / Nakamura, Hideki / Kawakami, Atsushi / Sano, Hajime / Ogawa, Yoko / Tsubota, Kazuo / Ryo, Koufuchi / Saito, Ichiro / Tanaka, Akihiko / Nakamura, Seiji / Takamura, Etsuko / Tanaka, Masao / Suzuki, Katsuya / Takeuchi, Tsutomu / Yamakawa, Noriyuki / Mimori, Tsuneyo / Ohta, Akiko / Nishiyama, Susumu / Yoshihara, Toshio / Suzuki, Yasunori / Kawano, Mitsuhiro / Tomiita, Minako / Tsuboi, Hiroto. ·a Department of Internal Medicine , University of Tsukuba , Ibaraki , Japan. · b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan. · c Division of Rheumatology, Department of Internal Medicine , Hyogo College of Medicine , Hyogo , Japan. · d Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences , Kyushu University , Fukuoka , Japan. · e The First Department of Internal Medicine , School of Medicine, University of Occupational and Environmental Health, Japan , Fukuoka , Japan. · f Department of Clinical Immunology and Rheumatology , Hiroshima University Hospital , Hiroshima , Japan. · g Unit of Translational Medicine, Department of Immunology and Rheumatology , Nagasaki University Graduate School of Biomedical Sciences , Nagasaki , Japan. · h Department of Ophthalmology , School of Medicine, Keio University , Tokyo , Japan. · i Department of Pathology , Tsurumi University School of Dental Medicine , Kanagawa , Japan. · j Department of Ophthalmology , Tokyo Women's Medical University, School of Medicine , Tokyo , Japan. · k Department of Advanced Medicine for Rheumatic Diseases , Kyoto University Graduate School of Medicine , Kyoto , Japan. · l Division of Rheumatology, Department of Internal Medicine , School of Medicine, Keio University , Tokyo , Japan. · m Department of Rheumatology and Clinical Immunology , Kyoto University Graduate School of Medicine , Kyoto , Japan. · n Department of Rheumatology , Kyoto-Katsura Hospital , Kyoto , Japan. · o Division of Public Health, Department of Social Medicine , Saitama Medical University , Saitama , Japan. · p Kurashiki Medical Center , Okayama , Japan. · q Department of Otorhinolaryngology , Tokyo Women's Medical University , Tokyo , Japan. · r Division of Rheumatology, Department of Cardiovascular and Internal Medicine , Kanazawa University Graduate School of Medicine , Ishikawa , Japan. · s Department of Allergy and Rheumatology , Chiba Children's Hospital , Chiba , Japan. ·Mod Rheumatol · Pubmed #29409370.

ABSTRACT: OBJECTIVES: The objective of this study is to develop clinical practice guideline (CPG) for Sjögren's syndrome (SS) based on recently available clinical and therapeutic evidences. METHODS: The CPG committee for SS was organized by the Research Team for Autoimmune Diseases, Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW), Japan. The committee completed a systematic review of evidences for several clinical questions and developed CPG for SS 2017 according to the procedure proposed by the Medical Information Network Distribution Service (Minds). The recommendations and their strength were checked by the modified Delphi method. The CPG for SS 2017 has been officially approved by both Japan College of Rheumatology and the Japanese Society for SS. RESULTS: The CPG committee set 38 clinical questions for clinical symptoms, signs, treatment, and management of SS in pediatric, adult and pregnant patients, using the PICO (P: patients, problem, population, I: interventions, C: comparisons, controls, comparators, O: outcomes) format. A summary of evidence, development of recommendation, recommendation, and strength for these 38 clinical questions are presented in the CPG. CONCLUSION: The CPG for SS 2017 should contribute to improvement and standardization of diagnosis and treatment of SS.

5 Review RANKL: A therapeutic target for bone destruction in rheumatoid arthritis. 2018

Tanaka, Sakae / Tanaka, Yoshiya / Ishiguro, Naoki / Yamanaka, Hisashi / Takeuchi, Tsutomu. ·a Department of Orthopaedic Surgery, Faculty of Medicine , The University of Tokyo , Tokyo , Japan. · b First Department of Internal Medicine , University of Occupational and Environmental Health , Fukuoka , Japan. · c Department of Orthopaedic Surgery , Nagoya University Graduate School of Medicine , Aichi , Japan. · d Institute of Rheumatology, Tokyo Women's Medical University , Tokyo , Japan. · e Division of Rheumatology, Department of Internal Medicine , Keio University School of Medicine , Tokyo , Japan. ·Mod Rheumatol · Pubmed #28880683.

ABSTRACT: Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by progressive joint destruction. Recent studies have indicated the critical involvement of osteoclasts in bone destruction in RA. The osteoclast differentiation factor receptor activator of NF-κB ligand (RANKL), which belongs to the tumor necrosis factor superfamily, plays a critical role in osteoclast differentiation and bone destruction in RA. Denosumab, an antibody against human RANKL, efficiently suppressed the progression of bone erosion in RA patients in randomized controlled studies, and is considered as a putative therapeutic option for preventing bone destruction in RA.

6 Review Stopping tumour necrosis factor-targeted biological DMARDs in rheumatoid arthritis. 2016

Tanaka, Yoshiya. ·The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan tanaka@med.uoeh-u.ac.jp. ·Rheumatology (Oxford) · Pubmed #27856656.

ABSTRACT: The combined use of MTX and biological DMARDs (bDMARDs) targeting TNF has revolutionized treatment of RA, and clinical remission becomes a realistic treatment goal. After sustained remission, discontinuation of bDMARDs without disease flare has been emerging as an important theme from the risk-benefit point of view and economic burden. According to several studies, approximately half of early RA patients could discontinue TNF-targeted bDMARDs without clinical flare and functional impairment after obtaining low disease activity or remission by treatment with bDMARDs and MTX. For established RA, however, fewer patients sustained remission or low disease activity after the discontinuation of bDMARDs, compared with early RA. The results were controversial among studies, and the percentage of patients who could successfully discontinue bDMARDs ranged from 13 to 48% at 1 year after discontinuation. From the adalimumab discontinuation without functional and radiographic damage progression following sustained remission study and the induction of remission by infliximab in RA study, deep remission at discontinuation was a key factor for maintaining the treatment holiday of bDMARDs in established RA patients. However, such early intensive treatment would have the potential for reducing drug-induced adverse effects and reducing long-term medical costs, although the risks of worsening clinical, structural and functional outcomes should be considered, with careful monitoring.

7 Review Recent Progress in JAK Inhibitors for the Treatment of Rheumatoid Arthritis. 2016

Nakayamada, Shingo / Kubo, Satoshi / Iwata, Shigeru / Tanaka, Yoshiya. ·The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahata-nishi, Kitakyushu, 807-8555, Japan. · The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahata-nishi, Kitakyushu, 807-8555, Japan. tanaka@med.uoeh-u.ac.jp. ·BioDrugs · Pubmed #27577235.

ABSTRACT: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovial inflammation and joint destruction. Considerable advance in the treatment of RA has been made following the advent of biological disease-modifying anti-rheumatic drugs (DMARDs). However, these biologics require intravenous or subcutaneous injection and some patients fail to respond to biological DMARDs or lose their primary response. Various cytokines and cell surface molecules bind to receptors on the cell surface, resulting in the activation of various cell signaling pathways, including phosphorylation of kinase proteins. Among these kinases, the non-receptor tyrosine kinase family Janus kinase (JAK) plays a pivotal role in the pathological processes of RA. Several JAK inhibitors have been developed as new therapies for patients with RA. These are oral synthetic DMARDs that inhibit JAK1, 2, and 3. One JAK inhibitor, tofacitinib, has already been approved in many countries. Results of phase III clinical trials using a JAK1/2 inhibitor, baricitinib, have shown feasible efficacy and tolerable safety. Both drugs are effective in patients who showed inadequate response to biological DMARDs as well as synthetic DMARDs. In addition, clinical phase III trials using filgotinib and ABT-494, specific JAK1 inhibitors, are currently underway. JAK inhibitors are novel therapies for RA, but further studies are needed to determine their risk-benefit ratio and selection of the most appropriate patients for such therapy.

8 Review Efficacy and safety of tofacitinib in patients with active rheumatoid arthritis: review of key Phase 2 studies. 2016

Fleischmann, Roy / Kremer, Joel / Tanaka, Yoshiya / Gruben, David / Kanik, Keith / Koncz, Tamas / Krishnaswami, Sriram / Wallenstein, Gene / Wilkinson, Bethanie / Zwillich, Samuel H / Keystone, Edward. ·Metroplex Clinical Research Center, Dallas, Texas, USA. · Center for Rheumatology, Albany Medical College, Albany, New York, USA. · First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. · Pfizer Inc., Groton, Connecticut, USA. · Pfizer Inc., New York, New York, USA. · Mount Sinai Hospital, Toronto, Ontario, Canada. ·Int J Rheum Dis · Pubmed #27451980.

ABSTRACT: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here, the safety and efficacy data from five Phase 2 studies of tofacitinib in patients with RA are summarized. Tofacitinib 1-30 mg twice daily was investigated, as monotherapy and in combination with methotrexate, in patients with RA. Tofacitinib 20 mg once daily was investigated in one study. Tofacitinib 5 and 10 mg twice daily were selected for investigation in Phase 3 studies; therefore, the efficacy and safety of tofacitinib 5 and 10 mg twice daily in Phase 2 studies are the focus of this review. Tofacitinib ≥ 5 mg twice daily was efficacious in a dose-dependent manner, with statistically significant and clinically meaningful reductions in the signs and symptoms of RA and patient-reported outcomes. The safety profile was consistent across studies. The efficacy and safety profile of tofacitinib in Phase 2 studies supported its further investigation and the selection of tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily for evaluation in Phase 3 studies.

9 Review Baricitinib for the treatment of rheumatoid arthritis. 2016

Kubo, Satoshi / Nakayamada, Shingo / Tanaka, Yoshiya. ·a The First Department of Internal Medicine , University of Occupational and Environmental Health , Fukuoka , Japan. ·Expert Rev Clin Immunol · Pubmed #27427830.

ABSTRACT: INTRODUCTION: Rheumatoid arthritis (RA) is characterized by systemic synovitis causing joint destruction. With the development of biological disease-modifying anti-rheumatic drugs (bDMARDs) and combination of conventional DMARDs, clinical remission is perceived as an appropriate and realistic goal in many patients. However, bDMARDs require intravenous or subcutaneous injection and some patients fail to respond to bDMARDs or lose their primary response. Under the circumstances, targeted synthetic DMARDs (tsDMARDs), which are orally available low-molecular weight products, have been emerging. Five phase 3 trials of Baricitinib, a JAK1 and JAK2 inhibitor, have been performed and showed high clinical efficacy in patients with active RA and naïve to sDMARDs or an inadequate response to sDMARDs, MTX or bDMARDs. There was a favorable response for clinical and functional parameters in studies with placebo, MTX and adalimumab as comparator. It is also reported that safety was tolerable within the limited study period. AREAS COVERED: We here review the recent progress in the development of baricitinib and its potential for the treatment of RA. Expert commentary: Although baricitinib is only one of the highly effective DMARDs that has a new mode of action, it will bring new concepts for rheumatology in the future.

10 Review [Tofacitinib for the treatment of rheumatoid arthritis]. 2016

Tanaka, Yoshiya. · ·Nihon Rinsho · Pubmed #27311188.

ABSTRACT: The combined use of synthetic disease-modifying anti-rheumatic drugs (sDMARDs) such as methotrexate and biological DMARDs (bDMARDs) has revolutionized treatment of rheumatoid arthritis (RA). Remission is now realistic targets, achieved by a large proportion of RA patients. However, bDMARDs are limited to intravenous or subcutaneous uses and orally available small but strong products have been developed. Oral administration of tofacitinib targeting the Janus kinase (JAK) is significantly effective than placebo in active RA patients with sDMARD-naïve, inadequately responsive to sDMARDs or TNF-inhibitors. The efficacy was rapid and as strong as adalimumab, a TNF-inhibitor. The common adverse events were related to infection, hematologic and hepatic disorders and association of tofacitinib with carcinogenicity and infections remains debated.

11 Review [New assessment method in rheumatoid arthritis]. 2016

Hirata, Shintaro / Tanaka, Yoshiya. · ·Nihon Rinsho · Pubmed #27311181.

ABSTRACT: To assess disease activity in rheumatoid arthritis (RA), several composite measures have been used. However, more objective indices have been desired due to subjectivity in conventional indices. The Multi-Biomarker Disease Activity(MBDA) score is a novel serum testing based disease activity score ranging 1-100, derived from pre-specified algorithms in combination with 12 biomarkers. The MBDA score not only reflects disease activity in RA, but also is predictive for radiographic progression and risk of flare after drug reduction. Here we review usefulness of the MBDA score in RA.

12 Review Tapering biologic and conventional DMARD therapy in rheumatoid arthritis: current evidence and future directions. 2016

Schett, Georg / Emery, Paul / Tanaka, Yoshiya / Burmester, Gerd / Pisetsky, David S / Naredo, Esperanza / Fautrel, Bruno / van Vollenhoven, Ronald. ·Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany. · Division of Rheumatic and Musculoskeletal Disease, Chapel Allerton Hospital, Leeds, UK. · Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany. · The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. · Duke University Medical Center, Medical Research Service, Durham, North Carolina, USA. · Department of Rheumatology, Hospital General Universitario Gregorio Marañón, Madrid, Spain. · Rheumatology Department, UPMC-GRC 08, Pierre Louis Institute for Epidemiology and Public Health-AP-HP, Pitie Salpetriere University Hospital, Paris, France. · ARC: Amsterdam Rheumatology and Immunology Center. ·Ann Rheum Dis · Pubmed #27261493.

ABSTRACT: Improvements in the control of inflammation in rheumatoid arthritis (RA) by conventional synthetic and biologic disease-modifying antirheumatic drugs (DMARDs) have led to a substantial change in the clinical outcomes of patients during the last 30 years. Current treatment can lead to sustained remission in some patients raising questions about the optimal management strategies in this subgroup of patients. Today, tapering of DMARDs and even their discontinuation appears as an interesting concept for achieving a more tailored and dynamic treatment approach of RA, especially in patients, who achieved full disease control by DMARD treatment. In this review article, current developments of DMARD tapering are discussed. The article provides an overview of existing studies on this topic and addresses new strategies to reach drug-free remission. Furthermore, concepts for defining patients eligible for DMARD tapering are described and potential future strategies in using biomarkers in predicting the risk for disease relapse after initiation of DMARD tapering are addressed. These findings are finally considered in light of the vision to achieve cure as an ultimate goal in patients with RA achieving full control of inflammation.

13 Review Progress in understanding the safety and efficacy of Janus kinase inhibitors for treatment of rheumatoid arthritis. 2016

Iwata, Shigeru / Tanaka, Yoshiya. ·a The First Department of Internal Medicine, School of Medicine , University of Occupational and Environmental Health, Japan , Kitakyushu , Japan. ·Expert Rev Clin Immunol · Pubmed #27253519.

ABSTRACT: INTRODUCTION: Treatment of rheumatoid arthritis (RA) has improved considerably following the advent of biologic disease-modifying anti-rheumatic drugs (DMARDs). However, these drugs require special storage and transportation. Janus kinase (JAK) inhibitors are oral synthetic DMARDs that inhibit the non-receptor tyrosine kinase family Janus kinase. Recently, many JAK inhibitors are being developed as new therapies for patients with RA. AREAS COVERED: In this article, we mainly review the efficacy and safety of JAK inhibitors currently under investigation. Tofacitinib has already been approved in 43 countries except in the EU. Results of three JAK inhibitors (baricitinib, decernotinib, and peficitinib) in phase III are consistent with that of tofacitinib. Tofacitinib and baricitinib were partially effective in patients who had an inadequate response to biological DMARDs. Expert commentary: JAK kinase inhibitors provide a new therapeutic approach for rheumatoid arthritis. Meanwhile, further studies are needed to determine their risk-benefit ratio and the most appropriate patients suitable for such therapy.

14 Review The changing landscape of biosimilars in rheumatology. 2016

Dörner, Thomas / Strand, Vibeke / Cornes, Paul / Gonçalves, João / Gulácsi, László / Kay, Jonathan / Kvien, Tore K / Smolen, Josef / Tanaka, Yoshiya / Burmester, Gerd R. ·Department of Medicine/Rheumatology and Clinical Immunology, Charité Universitätsmedizin, Berlin, Germany Deutsches Rheumaforschungszentrum (DRFZ), Berlin, Germany. · Division Immunology/Rheumatology, Stanford University School of Medicine, Palo Alto, California, USA. · Comparative Outcomes Group, Bristol, UK. · Faculty of Pharmacy at University of Lisbon, iMed- Research Institute for Medicines, Portugal. · Department of Health Economics, Corvinus University of Budapest, Budapest, Hungary. · Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School and UMass Memorial Medical Center, Worcester, Massachusetts, USA. · Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway. · Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria Department of Medicine, Hietzing Hospital, Vienna, Austria. · The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. · Department of Medicine/Rheumatology and Clinical Immunology, Charité Universitätsmedizin, Berlin, Germany. ·Ann Rheum Dis · Pubmed #26964144.

ABSTRACT: Biosimilars remain a hot topic in rheumatology, and some physicians are cautious about their application in the real world. With many products coming to market and a wealth of guidelines and recommendations concerning their use, there is a need to understand the changing landscape and the real clinical and health-economic potential offered by these agents. Notably, rheumatologists will be at the forefront of the use of biosimilar monoclonal antibodies/soluble receptors. Biosimilars offer cost savings and health gains for our patients and will play an important role in treating rheumatic diseases. We hope that these lower costs will compensate for inequities in access to therapy based on economic differences across countries. Since approved biosimilars have already demonstrated highly similar efficacy, it will be most important to establish pharmacovigilance databases across countries that are adequate to monitor long-term safety after marketing approval.

15 Review Current concepts in the management of rheumatoid arthritis. 2016

Tanaka, Yoshiya. ·The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan. ·Korean J Intern Med · Pubmed #26932398.

ABSTRACT: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammation and joint destruction that causes significant morbidity and mortality. However, the combined use of methotrexate, a synthetic disease-modifying antirheumatic drug (DMARD), and biologic DMARD has revolutionized treatment of RA. Clinical remission is now realistic targets, achieved by a large proportion of RA patients, and rapid and appropriate induction of remission by intensive treatment with biological DMARD and methotrexate is prerequisite to halt joint damage and functional disabilities. However, biological DMARD is limited to intravenous or subcutaneous uses and orally available small but strong molecules have been developed. Oral administration of tofacitinib targeting the Janus kinase (JAK) is significantly effective than placebo in active patients with methotrexatenaïve, inadequately responsive to methotrexate or tumor necrosis factor (TNF)-inhibitors. The efficacy was rapid and as strong as adalimumab, a TNF-inhibitor. Meanwhile, association of tofacitinib on carcinogenicity and malignancy is under debate and further investigation on post-marketing survey would be warranted. On the other hand, discontinuation of a biological DMARD without disease flare is our next goal and desirable from the standpoint of risk reduction and cost effectiveness, especially for patients with clinical remission. Recent reports indicate that more than half of early RA patients could discontinue TNF-targeted biological DMARD without clinical flare and functional impairment after obtaining clinical remission. Contrarily, for established RA, fewer patients sustained remission after the discontinuation of biological DMARD and "deep remission" at the discontinuation was a key factor to keep the treatment holiday of biological DMARD.

16 Review Evaluation of golimumab for the treatment of patients with active rheumatoid arthritis. 2016

Tanaka, Yoshiya / Senoo, Asako / Fujii, Hideji / Baker, Daniel. ·a The First Department of Internal Medicine, School of Medicine , University of Occupational & Environmental Health , Kitakyushu , Japan. · b Research & Development, Janssen Pharmaceutical K.K ., Tokyo , Japan. · c Janssen Research & Development , LLC , Spring House , PA , USA. ·Expert Opin Drug Metab Toxicol · Pubmed #26811250.

ABSTRACT: INTRODUCTION: Golimumab is a human anti-TNF monoclonal antibody that was derived from human antibody-transgenic mice. Golimumab demonstrated meaningful clinical benefit and tolerable safety in patients with active rheumatoid arthritis (RA) who were methotrexate (MTX)-naïve, or who inadequately responded to MTX or who had previously been treated with a TNF inhibitor. AREAS COVERED: This review summarizes published data on the clinical efficacy and safety for golimumab (including its pharmacodynamic and pharmacokinetic characteristics) from multiple global phase III and Japanese phase II/III clinical trials. In the long term extension of three Phase III studies with subcutaneous golimumab, the reported retention rate is high. EXPERT OPINION: Golimumab binds TNF with high affinity and can be delivered subcutaneously every 4 weeks. Like other IgG1 antibodies, FcγR functions suggests that antibody dependent cellular cytotoxicity is observed but the contribution of cell lysis to efficacy is unclear. Although anti-TNFα agents made it possible to achieve clinical remission in RA patients, there is still an unmet need to develop treatments that will enable them to discontinue all RA medication and maintain drug-free remission.

17 Review Disease control by regulation of P-glycoprotein on lymphocytes in patients with rheumatoid arthritis. 2015

Tsujimura, Shizuyo / Tanaka, Yoshiya. ·Shizuyo Tsujimura, Yoshiya Tanaka, the First Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, Kitakyushu 807-8555, Japan. ·World J Exp Med · Pubmed #26618109.

ABSTRACT: The main purpose of treatment of rheumatoid arthritis (RA) with disease modifying antirheumatic drugs (DMARDs) is to control activation of lymphocytes, although some patients do not respond adequately to such treatment. Among various mechanisms of multidrug resistance, P-glycoprotein (P-gp), a member of ATP-binding cassette transporters, causes drug-resistance by efflux of intracellular drugs. Certain stimuli, such as tumor necrosis factor-α, activate lymphocytes and induce P-gp expression on lymphocytes, as evident in active RA. Studies from our laboratories showed spontaneous nuclear accumulation of human Y-box-binding protein-1, a multidrug resistance 1 transcription factor, in unstimulated lymphocytes, and surface overexpression of P-gp on peripheral lymphocytes of RA patients with high disease activity. The significant correlation between P-gp expression level and RA disease activity is associated with active efflux of drugs from the lymphocyte cytoplasm and in drug-resistance. However, the use of biological agents that reduce P-gp expression as well as P-gp antagonists (e.g., cyclosporine) can successfully reduce the efflux of corticosteroids from lymphocytes in vitro, suggesting that both types of drugs can be used to overcome drug-resistance and improve clinical outcome. We conclude that lymphocytes activated by various stimuli in RA patients with highly active disease acquire P-gp-mediated multidrug resistance against corticosteroids and probably some DMARDs, which are substrates of P-gp. Inhibition/reduction of P-gp could overcome such drug resistance. Expression of P-gp on lymphocytes is a promising marker of drug resistance and a suitable therapeutic target to prevent drug resistance in patients with active RA.

18 Review Human mesenchymal stem cells as a tool for joint repair in rheumatoid arthritis. 2015

Tanaka, Yoshiya. ·The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. tanaka@med.uoeh-u.ac.jp. ·Clin Exp Rheumatol · Pubmed #26457506.

ABSTRACT: Rheumatoid arthritis (RA) is characterised with chronic inflammatory synovitis and progressive joint. Because damaged and/or deformed joints cannot be repaired, a novel treatment strategy aimed at both anti-inflammation and bone regeneration is a prerequisite. Mesenchymal stem cells (MSCs) can be easily isolated from various organs and possess multipotent capacity and exhibit immunoregulatory properties. Using human MSC derived from bone marrow and adipose tissue, we have clarified the following novel findings in vitro. 1) MSCs differentiated into osteoblasts or osteocytes under osteoblast-conditioned medium including the inflammatory stimuli such as IL-1. 2) The combination of IL-6 and soluble IL-6 receptor induced differentiation of MSCs to chondrocyte. 3) MSCs produced osteoprotegerin and inhibited osteoclastogenesis. Furthermore, we developed a local delivery system of MSCs by using nano-fibre scaffold. MSCs seeded on nano-fibre scaffold suppressed arthritis and joint destruction by inhibiting systemic inflammatory reaction and immune response through the induction of regulatory T cells and subsequent reduction in the production of anti-type II collagen antibody in vivo. Thus, our data may serve as a new strategy for MSC-based therapy in inflammatory diseases and an alternative delivery method for the treatment of damaged joints in RA.

19 Review Recent progress and perspective in JAK inhibitors for rheumatoid arthritis: from bench to bedside. 2015

Tanaka, Yoshiya. ·The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health Japan, Kitakyushu 807-8555, Japan tanaka@med.uoeh-u.ac.jp. ·J Biochem · Pubmed #26152731.

ABSTRACT: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovial inflammation and joint destruction. However, the combined use of synthetic disease-modifying anti-rheumatic drug (DMARD) such as methotrexate and a biological DMARD targeting tumour necrosis factor (TNF) has revolutionized treatment of RA. Clinical remission is a realistic target to treat and the maintenance of remission has produced significant improvements in structural and function outcomes. However, biological DMARDs are limited to intravenous or subcutaneous uses and orally available small but strong products have been developed. The multiple cytokines and cell surface molecules bind to receptors, resulting in the activation of various signalling, including phosphorylation of kinase proteins. Among multiple kinases, Janus kinase (JAK) plays pivotal roles in the pathological processes of RA. Tofacitinib, a small product targeting JAK, inhibits phosphorylation of JAK1 and JAK3, subsequent Stat1 and expression of Stat1-inducible genes, which contribute to efficient propagation of its anti-inflammatory effects for the treatment of RA. The primary targets of tofacitinib are dendritic cells, CD4(+) T cells such as Th1 and Th17 and activated B cells which leads to multi-cytokine targeting. Six global phase 3 studies revealed that oral administration of 5 or 10 mg tofacitinib was significantly effective than placebo with or without methotrexate in active RA patients with methotrexate-naïve, inadequately responsive to methotrexate or TNF-inhibitors. Therapeutic efficacy of tofacitinib was observed in a short term after administration and was as strong as adalimumab, a TNF-inhibitor. The most commonly observed adverse events were related to infection, hematologic, hepatic and renal disorders and association of tofacitinib with carcinogenicity and infections remains debated. Further investigation on post-marketing survey would help us understand the positioning of this drug.

20 Review [Mesenchymal stem cells for the treatment and repair of inflammatory arthritis]. 2015

Tanaka, Yoshiya / Sonomoto, Koshiro / Kondo, Masahiro / Oshita, Koichi / Zhang, Xiang-Mei / Fukuyo, Shunsuke / Yamaoka, Kunihiro. ·The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health. ·Nihon Rinsho Meneki Gakkai Kaishi · Pubmed #26016635.

ABSTRACT: Mesenchymal stem cells (MSCs) possess multipotent capacity and exhibit immunoregulatory properties. In particular, MSCs can be easily isolated from various organs, can differentiate into various types of cells and generate regulatory T cells. Using human MSC derived from bone marrow and adipose tissue, we have clarified the following novel findings in vitro. 1) MSCs differentiated into osteoblasts or osteocytes under osteoblast-conditioned medium including the inflammatory stimuli such as IL-1. 2) The combination of IL-6 and soluble IL-6 receptor induced differentiation of MSCs to chondrocyte, whereas IL-17 inhibited their differentiation. 3) MSCs highly produced osteoprotegerin and inhibited osteoclastogenesis. Furthermore, we developed a local delivery system of MSCs by using nano-fiber scaffold. MSCs seeded on nano-fiber scaffold suppressed arthritis and bone destruction due to inhibition of systemic inflammatory reaction and immune response by suppressing T cell proliferation and reducing anti-type II collagen antibody production in vivo. Thus, our data may serve as a new strategy for MSC-based therapy in inflammatory diseases and an alternative delivery method for the treatment of destruction of bone and joints.

21 Review Combination therapy for early rheumatoid arthritis: a treatment holiday perspective. 2015

Hirata, Shintaro / Tanaka, Yoshiya. ·The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi, Kitakyushu, 807-8555, Japan. ·Expert Rev Clin Pharmacol · Pubmed #25420554.

ABSTRACT: To date, the significance of early intervention with methotrexate and biological disease-modifying anti-rheumatic drugs for rheumatoid arthritis (RA) has not been realized. Longitudinal safety and cost have arisen as new concerns. The concept of a treatment holiday, drug discontinuation after achieving remission, may solve these problems. The authors performed a systematic literature review and identified 13 reports from 10 studies (TNF20, BeSt, OPITMA, HIT-HARD, IMPROVED, PRIZE, IDEA, EMPIRE, tREACH and AVERT) for early RA (≤2 years). Eight out of 13 reports (61.5%) were published in 2013 or 2014, indicating emerging interest in recent years. Also, the authors performed a sub-analysis of the HONOR study (n = 51) to compare early (≤2 years) and established RA. The proportions of remission (REM) and low disease activity were higher in early RA (REM: 63.0 vs 33.3%, p = 0.0346; low disease activity: 77.8 vs 45.8%, p = 0.0185). In conclusion, early intervention is beneficial for successful treatment holiday, which may lead to risk and cost reduction. However, further investigation is required.

22 Review Acquiring chondrocyte phenotype from human mesenchymal stem cells under inflammatory conditions. 2014

Kondo, Masahiro / Yamaoka, Kunihiro / Tanaka, Yoshiya. ·The First Department of Internal Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan. Kondo.Masahiro@mc.mt-pharma.co.jp. · The First Department of Internal Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan. yamaoka@med.uoeh-u.ac.jp. · The First Department of Internal Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan. tanaka@med.uoeh-u.ac.jp. ·Int J Mol Sci · Pubmed #25407530.

ABSTRACT: An inflammatory milieu breaks down the cartilage matrix and induces chondrocyte apoptosis, resulting in cartilage destruction in patients with cartilage degenerative diseases, such as rheumatoid arthritis or osteoarthritis. Because of the limited regenerative ability of chondrocytes, defects in cartilage are irreversible and difficult to repair. Mesenchymal stem cells (MSCs) are expected to be a new tool for cartilage repair because they are present in the cartilage and are able to differentiate into multiple lineages of cells, including chondrocytes. Although clinical trials using MSCs for patients with cartilage defects have already begun, its efficacy and repair mechanisms remain unknown. A PubMed search conducted in October 2014 using the following medical subject headings (MeSH) terms: mesenchymal stromal cells, chondrogenesis, and cytokines resulted in 204 articles. The titles and abstracts were screened and nine articles relevant to "inflammatory" cytokines and "human" MSCs were identified. Herein, we review the cell biology and mechanisms of chondrocyte phenotype acquisition from human MSCs in an inflammatory milieu and discuss the clinical potential of MSCs for cartilage repair.

23 Review Intensive intervention can lead to a treatment holiday from biological DMARDs in patients with rheumatoid arthritis. 2014

Tanaka, Yoshiya / Hirata, Shintaro. ·The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health Japan, 1-1 Iseigaoka, Kitakyushu, 807-8555, Japan, tanaka@med.uoeh-u.ac.jp. ·Drugs · Pubmed #25389048.

ABSTRACT: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammation and joint destruction that causes significant morbidity and mortality. However, the combined use of methotrexate (MTX), a synthetic disease-modifying anti-rheumatic drug (sDMARD) and biological DMARDs (bDMARDs) has revolutionized treatment of RA and clinical remission or low disease activity (LDA) are now realistic targets, achieved by a large proportion of RA patients. We are now in a position to evaluate if it is possible to maintain remission or LDA while at the same time reducing the burden of treatment on the patient and healthcare system. Data are emerging from large, well-conducted studies designed to answer this question, shedding light on which patient populations and treatment algorithms can survive treatment discontinuation or tapering with low risk of disease flare. For early RA, approximately half of early RA patients could discontinue TNF-targeted bDMARDs without clinical flare and functional impairment after obtaining clinical remission by bDMARDs with MTX. In contrast, for established RA, fewer patients sustained remission or LDA after the discontinuation of bDMARDs and "deep remission" at the discontinuation was a key factor to maintain the treatment holiday of bDMARDs. Thus, this article provides a brief outline on withdrawing or tapering bDMARDs once patients have achieved remission or LDA in RA.

24 Review [An approach to bone and cartilage repair of rheumatoid arthritis by mesenchymal stem cells]. 2014

Sonomoto, Koshiro / Yamaoka, Kunihiro / Tanaka, Yoshiya. ·First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan. ·J UOEH · Pubmed #24930879.

ABSTRACT: Rheumatoid arthritis (RA) is an autoimmune disease represented by chronic inflammation and following structural damage at the articular joints. Progression of the disease causes disability and subsequent early retirement or a care-requiring condition. Although new agents have the potential of complete inhibition of joint damage, there is still a considerable number of patients with progressed joint damage who couldn't receive the benefits of these agents because of the long duration of their disease or uncontrollable disease activity. Thus, a new treatment tool for RA aiming at joint repair is necessary. Mesenchymal stem cells (MSCs) are known to build bone and cartilage, and also have immunosuppressive ability. We have considered MSCs as a new treatment tool of RA, and have reported that MSCs suppress osteoclastogenesis. More recently, we also reported that inflammation induces osteogenesis and suppresses the chondrogenesis of MSCs. An investigation of a new delivery system of MSCs to the target lesion is now ongoing. The data from this investigation suggest that MSCs can be a new application in the treatment of RA.

25 Review [Biologic agents for the treatment of rheumatic diseases]. 2014

Tanaka, Yoshiya. ·The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan. ·Clin Calcium · Pubmed #24870843.

ABSTRACT: Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by chronic synovitis and bone damage. Bone homeostasis is maintained by a balance between bone resorption and bone formation. It is also involved by immune systems and imbalance in immune system often results in pathological processes such as joint destruction as well as secondary osteoporosis. Proinflammatory cytokines such as TNF and IL-6 cause an imbalance in bone metabolism via direct and/or indirect effects on osteoclasts. However, the combination of methotrexate and biologic DMARDs targeting TNF and IL-6 have revolutionized the treatment of RA, producing significant improvements in clinical, radiographic, and functional outcomes that were not previously observed. Such progress in the treatment of RA has been expanded to other joint diseases including psoriatic arthritis, spodylarthritis and so on.

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