Hitoshi Kohsaka

Tokyo Medical and Dental University, Edo, Tōkyō, Japan

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Publications (137)514.38 Total impact

  • Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):1070.3-1071. DOI:10.1136/annrheumdis-2015-eular.2544 · 10.38 Impact Factor
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    ABSTRACT: Objective To investigate whether leucine-rich alpha-2 glycoprotein (LRG) could be a disease activity biomarker of rheumatoid arthritis (RA) during IL-6 blockade.Methods Serum LRG levels in RA patients treated with tocilizumab for 24 weeks (n=59) were determined by ELISA. RA disease activity was evaluated by the Clinical Disease Activity Index (CDAI). Receiver operating characteristics (ROC) curve analysis was used to examine diagnostic performance of LRG and other biomarkers. Monkeys with experimental autoimmune arthritis were treated by anti-IL-6 receptor antibody and their swollen joint counts, joint pathological changes, and blood levels of CRP and LRG were evaluated.ResultsAmong tocilizumab-treated RA patients, patients with active disease (CDAI > 2.8) had significantly high serum LRG levels compared to those in remission. ROC curve analysis suggests that LRG is more useful than CRP, ESR or MMP-3 in discriminating between CDAI remission and active disease during therapy with tocilizumab. In arthritic monkeys with IL-6 blockade, LRG levels correlated with joint scores better than CRP. Histological analysis of joints revealed that LRG levels correlated significantly with granulomatous tissue formation, cartilage degeneration and bone destruction in CRP-low monkeys during IL-6 blockade.Conclusion Under IL-6 inhibition, LRG was more useful than other biomarkers for discriminating active disease in human RA and detecting joint inflammation in arthritic animals. LRG may serve as a convenient biomarker for RA during IL-6 blockade. This article is protected by copyright. All rights reserved.
    04/2015; DOI:10.1002/art.39164
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    ABSTRACT: To evaluate the efficacy and safety of switching from intravenous (IV) tocilizumab (TCZ) to subcutaneous (SC) TCZ monotherapy in rheumatoid arthritis patients. Patients who had completed 24 weeks' TCZ-SC (162 mg/2 weeks) or TCZ-IV (8 mg/kg/4 weeks) monotherapy in the MUSASHI study double-blind period were enrolled in an 84-week open-label extension period (OLE). All received TCZ-SC (162 mg/2 weeks) monotherapy. Effects of the IV-to-SC switch were evaluated at week 36 (12 weeks after switching). Overall, 319 patients received at least one dose of TCZ-SC during OLE; 160 switched from TCZ-IV to TCZ-SC (TCZ IV/SC) and 159 continued TCZ-SC (TCZ SC/SC). DAS28-ESR clinical remission rates were 62.5% (100/160) for TCZ IV/SC and 50.0% (79/158) for TCZ SC/SC at week 24, and were maintained at 62.5% (100/160) and 57.0% (90/158), respectively, at week 36. In the TCZ IV/SC group, 9% (9/100) of patients who had achieved remission at week 24 could not maintain remission at week 36. In TCZ IV/SC patients weighing ≥ 70 kg, the percentage with sufficient serum TCZ concentration (≥1 μg/mL) decreased from 90.9% (10/11) at week 24 to 45.5% (5/11) at week 36. Overall safety profiles were similar in TCZ IV/SC and TCZ SC/SC except for mild injection site reactions in TCZ IV/SC. Efficacy is adequately maintained in most patients switching from TCZ-IV (8 mg/kg/4 weeks) to TCZ-SC (162 mg/2 weeks) monotherapy. Patients receiving TCZ-IV can switch to TCZ-SC without serious safety concerns. Clinical efficacy may be reduced after switching in some high-body-weight patients. This article is protected by copyright. All rights reserved. © 2015 American College of Rheumatology.
    04/2015; DOI:10.1002/acr.22598
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    ABSTRACT: Pulmonary infections (PI) are leading causes of death in patients with connective tissue diseases (CTD). The PREVENT study (Pulmonary infections in patients receiving immunosuppressive treatment for CTD) assessed risk of PI in patients with active CTD in the contemporary era of advanced immunosuppressive therapy. In patients who started corticosteroids (n = 763), conventional immunosuppressants or biologics for active CTD were enrolled. Clinical and laboratory data, usage of drugs, and occurrence of PI were collected for 12 months. Baseline risk factors were investigated using Cox regression analysis. A nested case-control (NCC) study was performed with 1:2 matched case-control pairs to assess the risk for each drug category. During the observation period, 32 patients died (4.2%) and 66 patients were lost to followup (8.6%). Patients with PI (n = 61, 8%) had a significantly worse accumulated survival rate than patients without (p < 0.01). Cox hazard regression analysis using baseline data showed that these factors were significantly associated with PI: age ≥ 65 years (HR 3.87, 95% CI 2.22-6.74), ≥ 20 pack-years of smoking (2.63, 1.37-5.04), higher serum creatinine level (1.21, 1.05-1.41 per 1.0 mg/dl increase), and maximum prednisolone (PSL) dose during the first 2 weeks of treatment (2.81, 1.35-5.86 per 1.0 mg/kg/day increase). Logistic regression analysis by an NCC study revealed that maximum PSL dose within 14 days before PI (OR 4.82, 95% CI 1.36-17.01 per 1.0 mg/dl increase; 2.57, 1.28-5.16 if ≥ 0.5 mg/kg/day) was significantly associated with the events, while other immunosuppressants were not. Physicians should be aware of the higher risks for corticosteroids of PI than other immunosuppressants and assess these risk factors before immunosuppressive treatment, to prevent PI.
    The Journal of Rheumatology 02/2015; 42(4). DOI:10.3899/jrheum.140778 · 3.17 Impact Factor
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    ABSTRACT: It is suggested that polymyositis, an autoimmune inflammatory myopathy, is mediated by autoaggressive CD8 T cells. Skeletal muscle C protein is a self-antigen that induces C protein-induced myositis, a murine model of polymyotitis. To establish a new murine model of myosits inducible with a single CD8 T cell epitope peptide that derives from the C protein, 3 internet-based prediction systems were employed to identify 24 candidate peptides of the immunogenic fragment of the C protein and bind theoretically to major histocompatibility complex (MHC) class I molecules of C57BL/6 (B6) mice. RMA-S cell assay revealed that a HILIYSDV peptide, amino acid position 399 - 406 of the C protein, had the highest affinity to the H2-K(b) molecules. Transfer of mature bone marrow-derived dendritic cells pulsed with HILIYSDV induced myositis in naïve B6 mice. This myositis was suppressed by anti-CD8 depleting antibodies but not by anti-CD4 depleting antibodies. Because this myositis model is mediated by CD8 T cells independently of CD4 T cells, it should be a useful tool to investigate pathology of polymyositis and develop therapies targeting CD8 T cells. © The Japanese Society for Immunology. 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
    International Immunology 01/2015; 27(7). DOI:10.1093/intimm/dxv001 · 3.18 Impact Factor
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    ABSTRACT: Objective. To discern if injury and regeneration of the skeletal muscles induce inflammatory milieu that facilitates development and relapse of autoimmune myositis.Methods. The quadriceps of C57BL/6 mice were injured with bupivacaine (BPVC) and evaluated histologically. Macrophages and regenerating myofibers in the treated muscles and differentiating C2C12 myotubes were examined for cytokine expression. Mice were immunized with C protein fragments at the tail bases and right hind footpads (day 0) to evoke systemic anti-C-protein immunity and to induce local myositis in the right hindlimbs. The contralateral quadriceps were injured with BPVC or phosphate buffered saline (PBS) at day 7, or after spontaneous regression of myositis (day 42). The quadriceps from unimmunized mice were injured with BPVC at day 7. The muscles were examined histologically 14 days after the treatments.Results. The BPVC-injured muscles had macrophage infiltration most abundantly at 3 days after the injection with emergence of regenerating fibers from 5 days. The macrophages expressed inflammatory cytokines including tumor necrosis factor α, interleukin-1β, and chemokine (C-C motif) ligand 2. Regenerating myofibers and C2C12 myotubes also expressed the cytokines. The BPVC-injected muscles from unimmunized mice had regenerating myofibers with resolved cell infiltration 14 days after the treatment. In the mice preimmunized with C protein fragments, the muscles injured with BPVC, but not with PBS, at day 7 as well as at day 42 accompanied myositis with CD8+ T cell infiltration.Conclusion. Injury and regeneration could set up inflammatory milieu in the muscles and facilitate development and relapse of autoimmune myositis. This article is protected by copyright. All rights reserved.
    01/2015; 67(4). DOI:10.1002/art.39017
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    ABSTRACT: In this study, we investigated the relationship between several growth factors and inflammation development. Serum concentrations of epiregulin, amphiregulin, betacellulin, TGF-α, fibroblast growth factor 2, placental growth factor (PLGF), and tenascin C were increased in rheumatoid arthritis patients. Furthermore, local blockades of these growth factors suppressed the development of cytokine-induced arthritis in mice by inhibiting chemokine and IL-6 expressions. We found that epiregulin expression was early and followed by the induction of other growth factors at different sites of the joints. The same growth factors then regulated the expression of epiregulin at later time points of the arthritis. These growth factors were increased in patients suffering from multiple sclerosis (MS) and also played a role in the development of an MS model, experimental autoimmune encephalomyelitis. The results suggest that the temporal expression of growth factors is involved in the inflammation development seen in several diseases, including rheumatoid arthritis and MS. Therefore, various growth factor pathways might be good therapeutic targets for various inflammatory diseases. Copyright © 2015 by The American Association of Immunologists, Inc.
    The Journal of Immunology 01/2015; 194(3):1039-46. DOI:10.4049/jimmunol.1400562 · 5.36 Impact Factor
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    ABSTRACT: A 30-year-old woman had suffered from recurrent and self-limiting fevers since childhood. Although she had no mutations in the exons or introns of the tumor necrosis factor (TNF) receptor superfamily member 1A gene, her clinical characteristics were consistent with those of TNF receptor-associated periodic syndrome (TRAPS). She did not respond to treatment with etanercept, although tocilizumab therapy was successful, subsequently ameliorating her symptoms and preventing further inflammatory attacks. Interleukin-6 blocking therapy should be considered as a new alternative treatment in patients with TRAPS who do not respond to etanercept.
    Internal Medicine 01/2015; 54(16):2069-72. DOI:10.2169/internalmedicine.54.3371 · 0.97 Impact Factor
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    ABSTRACT: IntroductionBiological drugs are effective in patients with rheumatoid arthritis (RA), but increase severe infections. The CC chemokine receptor (CCR) 9 antagonist was effective for Crohn¿s disease without critical adverse effects including infections in clinical trials. The present study was carried out to explore the pathogenic roles of chemokine (C-C motif) ligand (CCL) 25 and its receptor, CCR9 in autoimmune arthritis and to study if the CCR9 antagonist could be a new treatment for RA.MethodsCCL25 and CCR9 expression was examined with immunohistochemistry and Western blotting. Concentration of interleukin (IL)-6, matrix metalloproteinase (MMP)-3 and tumor necrosis factor (TNF)-¿ was measured with enzyme-linked immunosorbent assays. Effects of abrogating CCR9 on collagen-induced arthritis (CIA) was evaluated using CCR9-deficient mice or the CCR9 antagonist, CCX8037. Fluorescence labeled-CD11b+ splenocytes from CIA mice were transferred to recipient CIA mice and those infiltrating into the synovial tissues of the recipient mice were counted.ResultsCCL25 and CCR9 proteins were found in the RA synovial tissues. CCR9 was expressed on macrophages, fibroblast-like synoviocytes (FLS) and dendritic cells in the synovial tissues. Stimulation with CCL25 increased IL-6 and MMP-3 production from RA FLS, and IL-6 and TNF-¿ production from peripheral blood monocytes. CIA was suppressed in CCR9-deficient mice. CCX8037 also inhibited CIA and the migration of transferred CD11b+ splenocytes into the synovial tissues.Conclusion The interaction between CCL25 and CCR9 may play important roles in cell infiltration into the RA synovial tissues and inflammatory mediator production. Blocking CCL25 or CCR9 may represent a novel safe therapy for RA.
    Arthritis Research & Therapy 09/2014; 16(5):445. DOI:10.1186/s13075-014-0445-9 · 3.75 Impact Factor
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    ABSTRACT: Objective Biological disease-modifying antirheumatic drugs (DMARDs) that inhibit aberrant immune reactions in rheumatoid arthritis (RA) cannot induce complete remission in all patients. Combination therapies using two biological DMARDs have failed to exert additive effects and increased serious infections. We have found that cell cycle inhibition of synovial fibroblasts with cyclin-dependent kinase (CDK) inhibitors ameliorated the disease in animal models of RA without attenuating acquired immunity. The objective of this study was to determine whether a clinically well-tolerated selective CDK 4/6 inhibitor (CDKI), palbociclib, is effective and whether combination with cytokine blockers acts additively without enhancing immune suppression. Methods The effects of CDKI on haematopoiesis and physical and behavioural findings in mice were evaluated. Mice with collagen-induced arthritis (CIA) were treated with CDKI, etanercept or anti-interleukin (IL)-6 receptor antibody (MR16-1) alone or with a combination of CDKI with etanercept or MR16-1. Their clinical, histological and radiographic scores, serum anti-(type II collagen (CII)) antibody levels and proliferative responses of lymph node cells to CII were determined. Results Although CDKI induced marginal myelosuppression, it was well tolerated and ameliorated CIA dose-dependently. The combinations of low-dose CDKI and either tumour necrosis factor-α or IL-6 blocker enhanced the antiarthritic effects additively. The addition of CDKI to either cytokine blocker did not affect the levels of anti-CII antibodies and proliferative responses of lymphocytes to CII. Conclusions A clinically well-tolerated CDK4/6 inhibitor exerted antiarthritic effects in this mouse model. By combining therapeutic agents targeting immune reaction and synovial proliferation, we have demonstrated for the first time that two molecular targeting treatments act additively and may not increase immune suppression.
    Annals of the Rheumatic Diseases 08/2014; DOI:10.1136/annrheumdis-2014-205566 · 10.38 Impact Factor
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    ABSTRACT: Background Some of cannabinoids, which are chemical compounds contained in marijuana, are immunosuppressive. One of the receptors, CB receptor 1 (CB1), is expressed predominantly by the cells in the central nervous system, whereas CB receptor 2 (CB2) is expressed primarily by immune cells. Theoretically, selective CB2 agonists should be devoid of psychoactive effects. In this study, we investigated therapeutic effects of a selective CB2 agonist on arthritis. Methods The expression of CB2 was analyzed with immunohistochemistry and Western blotting. Interleukin (IL)-6, matrix metalloproteinase-3 (MMP-3), and chemokine (C-C motif) ligand 2 (CCL2) were quantified with enzyme-linked immunosorbent assays (ELISA). Osteoclastogenesis was assessed with tartrate-resistant acid phosphatase staining and the resorption of coated-calcium phosphate. Effect of JWH133, a selective CB2 agonist, on murine collagen type II (CII)-induced arthritis (CIA) was evaluated with arthritis score, and histological and radiographic changes. IFN-γ and IL-17 production by CII-stimulated splenocytes and serum anti-CII Ab were analyzed by ELISA. Results Immunohistochemistry showed that CB2 was expressed more in the synovial tissues from the rheumatoid joints than in those from the osteoarthritis joints. CB2 expression on RA FLS was confirmed with Western blot analysis. JWH133 inhibited IL-6, MMP-3, and CCL2 production from tumor necrosis factor-α-stimulated fibroblast-like synoviocytes (FLS) derived from the rheumatoid joints, and osteoclastogenesis of peripheral blood monocytes. Administration of JWH133 to CIA mice reduced the arthritis score, inflammatory cell infiltration, bone destruction, and anti-CII IgG1 production. Conclusion The present study suggests that a selective CB2 agonist could be a new therapy for RA that inhibits production of inflammatory mediators from FLS, and osteoclastogenesis.
    BMC Musculoskeletal Disorders 08/2014; 15(1):275. DOI:10.1186/1471-2474-15-275 · 1.90 Impact Factor
  • Waka Yokoyama · Kazuki Takada · Nobuyuki Miyasaka · Hitoshi Kohsaka
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    ABSTRACT: A 64-year-old woman presented with an acute onset of myelitis and optic neuritis after 47 months of etanercept use for rheumatoid arthritis. Etanercept was discontinued and pulse methylprednisolone therapy (1000 mg/day for 3 days) was started, followed by a quick and complete resolution. Demyelination associated with antitumor necrosis factor agents, reported to develop mostly from 1 week to 12 months after the initiation of the agents, could develop after a few years and thus warrants vigilant monitoring.
    Case Reports 08/2014; 2014(aug01 1). DOI:10.1136/bcr-2014-205779
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    ABSTRACT: Objective. To investigate the role of adhesion molecules in C protein-induced myositis (CIM), a murine model for polymyositis (PM).Methods. CIM was induced in wild type mice, L-selectin-deficient (L-selectin-/-) mice, ICAM-1-deficient (ICAM-1-/-) mice, and both L-selectin- and ICAM-1-deficient (L-selectin-/-ICAM-1-/-) mice. The severity of myositis, inflammatory cell infiltration, and mRNA expression in the inflamed muscles were examined. The effect of dendritic polyglycerol sulfate (dPGS), a synthetic inhibitor that suppresses the function of L-selectin and endothelial P-selectin, was also examined.Results. L-selectin-/- mice and L-selectin-/-ICAM-1-/- mice developed significantly less severe myositis compared to wild type mice, while ICAM-1 deficiency did not inhibit the development of myositis. L-selectin-/- mice transferred with wild type T cells developed myositis. Wild type mice treated with dPGS significantly diminished the severity of myositis compared to control-treated wild type mice.Conclusions. These data indicate that L-selectin plays a major role in the development of CIM, whereas ICAM-1 plays a lesser, if any, role in the development of CIM. L-selectin-targeted therapy may be a candidate for the treatment of PM. © 2014 American College of Rheumatology.
    07/2014; 66(7):1864-1871. DOI:10.1002/art.38630
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    ABSTRACT: Introduction C-X-C motif chemokine 10 (CXCL10) is a chemokine that plays a critical role in the infiltration of T cells in autoimmune diseases and is reported to be expressed in muscle tissue of polymyositis. To determine the therapeutic efficacy of CXCL10 blockade, we investigated the role of CXCL10 and the effect of anti-CXCL10 antibody treatment in C protein-induced myositis (CIM), an animal model of polymyositis. Methods CIM was induced with human skeletal muscle C protein fragment in female C57BL/6 mice. Immunohistochemistry of CXCL10 and C-X-C motif chemokine receptor 3 (CXCR3) and measurement of serum CXCL10 were performed. Cell surface markers and interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) in CIM lymph node cells was investigated by flow cytometry. Mice with CIM were treated with anti-CXCL10 antibody or control antibody (anti-RVG1) and the inflammation in muscle tissue was assessed. Results Immunohistochemistry showed increased expression of CXCL10 and CXCR3 in the inflammatory lesions of muscle in CIM. Especially, CD8+ T cells invading myofiber expressed CXCR3. Serum level of CXCL10 was increased in CIM compared to the level in normal mice (normal mouse, 14.3 ± 5.3 pg/ml vs. CIM, 368.5 ± 135.6 pg/ml, P < 0.001). CXCR3 positivity in CD8+ T cells was increased compared to that of CD4+ T cells in the lymph node cells of CIM (CXCR3+ among CD8+ T cell, 65.9 ± 2.1% vs. CXCR3+ among CD4+ T cell, 23.5 ± 4.7%, P <0.001). Moreover, IFN-γ+ cells were increased among CXCR3+CD8+ T cells compared to CXCR3–CD8+ T cells (CXCR3+CD8+ T cell, 28.0 ± 4.2% vs. CXCR3-CD8+ T cell, 9.5 ± 1.5%, P = 0.016). Migration of lymph node cells was increased in response to CXCL10 (chemotactic index was 1.91 ± 0.45). CIM mice treated with anti-CXCL10 antibody showed a lower inflammation score in muscles than those with anti-RVG1 (median, anti-CXCL10 treatment group, 0.625 vs. anti-RVG1 treatment group, 1.25, P = 0.007). Conclusions CXCL10/CXCR3 expression was increased in the inflammation of CIM model and its blockade suppressed inflammation in muscle.
    Arthritis Research & Therapy 06/2014; 16(3):R126. DOI:10.1186/ar4583 · 3.75 Impact Factor
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    ABSTRACT: In addition to the pivotal roles of mast cells in allergic diseases, recent data suggest that mast cells play crucial roles in a variety of autoimmune responses. However, their roles in the pathogenesis of autoimmune skeletal muscle diseases have not been clarified despite their distribution in skeletal muscle. Therefore, the objective of this study is to determine the roles of mast cells in the development of autoimmune skeletal muscle diseases. The number of mast cells in the affected muscle was examined in patients with dermatomyositis (DM) or polymyositis (PM). The susceptibility of mast cell-deficient WBB6F1-KitW/KitWv mice (W/Wv mice) to a murine model of polymyositis, C protein-induced myositis (CIM), was compared with that of wild-type (WT) mice. The effect of mast cell reconstitution with bone marrow-derived mast cells (BMMCs) on the susceptibility of W/Wv mice to CIM was also evaluated. The number of mast cells in the affected muscle increased in patients with PM as compared to patients with DM. W/Wv mice exhibited significantly reduced disease incidence and histological scores of CIM as compared with WT mice. The number of CD8+ T cells and macrophages in the skeletal muscles of CIM decreased in W/Wv mice compared to WT mice. Engraftment of BMMCs restored the incidence and histological scores of CIM in W/Wv mice. Vascular permeability in the skeletal muscle was elevated in WT mice but not in W/Wv mice upon CIM induction. Mast cells are involved in the pathogenesis of inflammatory myopathy.
    Arthritis research & therapy 03/2014; 16(2):R72. DOI:10.1186/ar4512 · 3.75 Impact Factor
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    ABSTRACT: Background CXCL10 (also called interferon-γ-inducible protein 10 [IP-10]) is a chemokine that plays a critical role in the infiltration of T cell in autoimmune disease such as RA and SLE. CXCL10 is reported to be expressed in muscle tissue of polymyositis. Objectives We investigated the role of CXCL10 and the effect of CXCL10 blockade in C protein-induced myositis, an animal model of polymyositis. Methods C protein-induced myositis model was induced with human skeletal C protein fragment in 8-week-old female C57BL/6 mice. Immunohistochemistry was performed to detect CXCL10 and CXCR3, its receptor in muscle tissue. CXCR3 in mouse splenocyte was investigated by flow cytometry. Migration assay of mouse splenocyte was performed with 5 μm pore transwell system. Mice with C protein-induced myositis were treated with anti-CXCL10 antibody or control IgG 8 days after the induction of myositis and the inflammation in muscle tissue was assessed 3 week after the induction. Results Immunohistochemistry showed the expression of CXCL10 and CXCR3 in the muscle of C protein-induced myositis. Flow cytometry demonstrated increased CXCR3+CD4+ T cells (normal mice, 14.14%±1.09% vs. C protein-induced myositis, 37.50%±5.63%) and CXCR3+CD8+ T cells (normal mice, 35.55±2.41% vs. C protein-induced myositis, 79.00%±0.89%) in C protein-induced myositis. Moreover, it was showed that IFN-γ+ cells were increased among CXCR3+CD8+ T cells compared to CXCR3-CD8+ T cells (CXCR3+CD8+ T cell, 28.0 ± 4.2% vs. CXCR3-CD8+ T cell, 9.5 ± 1.5%, p = 0.016). Migration of splenocyte was increased in response to CXCL10 (chemotactic index=1.91±0.45). Treatment with anti-CXCL10 antibody (n=10) showed less inflammation score in muscles than treatment with control IgG (n=10; median [range], anti IP-10, 0.75 [0.25-2.00] vs. control IgG, 1.43 [1.125-4.25], p=0.045). Conclusions CXCL10 was expressed in the inflammation of C protein-induced myositis model and its blockade suppressed inflammation in muscle. Disclosure of Interest None Declared
    Annals of the Rheumatic Diseases 01/2014; 72(Suppl 3):A373-A373. DOI:10.1136/annrheumdis-2013-eular.1143 · 10.38 Impact Factor
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    ABSTRACT: Objective Autoantibodies to aminoacyl-tRNA synthetases (ARSs) are useful in the diagnosis of idiopathic inflammatory myopathy (IIM) with interstitial pneumonia (IP). We developed an enzyme-linked immunosorbent assay (ELISA) system using a mixture of recombinant ARS antigens and tested its utility in a multicenter study. Methods: We prepared six recombinant ARSs: GST-Jo-1, His-PL-12, His-EJ and GST-KS expressed in Escherichia coli, and His-PL-7 and His-OJ expressed in Hi-5 cells. After confirming their antigenic activity, with the exception of His-OJ, we developed our ELISA system in which the five recombinant ARSs (without His-OJ) were mixed. Efficiency was confirmed using the sera from 526 Japanese patients with connective tissue disease (CTD) (IIM n = 250, systemic lupus erythematosus n = 91, systemic sclerosis n = 70, rheumatoid arthritis n = 75, Sjögren’s syndrome n = 27 and other diseases n = 13), 168 with idiopathic interstitial pneumonia (IIP) and 30 healthy controls collected from eight institutes. IIPs were classified into two groups; idiopathic pulmonary fibrosis (IPF) (n = 38) and non-IPF (n = 130). Results were compared with those of RNA immunoprecipitation. Results: Sensitivity and specificity of the ELISA were 97.1% and 99.8%, respectively when compared with the RNA immunoprecipitation assay. Anti-ARS antibodies were detected in 30.8% of IIM, 2.5% of non-myositis CTD, and 10.7% of IIP (5.3% of IPF and 12.3% of non-IPF). Anti-ARS-positive non-IPF patients were younger and more frequently treated with glucocorticoids and/or immunosuppressants than anti-ARS-negative patients. Conclusion: A newly established ELISA detected anti-ARS antibodies as efficiently as RNA immunoprecipitation. This system will enable easier and wider use in the detection of anti-ARS antibodies in patients with IIM and IIP.
    PLoS ONE 01/2014; 9(1):e85062. DOI:10.1371/journal.pone.0085062 · 3.23 Impact Factor
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    ABSTRACT: We describe a patient who developed fever, bilateral otitis media, destructive necrosis of the nasal cavity and multiple lung nodules. The patient fulfilled the American College of Rheumatology (ACR) classification criteria for Wegener’s granulomatosis (WG) and was also diagnosed as having WG by using the ACR classification tree. However, the diagnosis of T cell lymphoma was finally made by cervical lymph node biopsy, 2 years after disease onset. Rheumatologists should therefore aware of the pitfall of using diagnostic criteria and repetitive biopsy is strongly recommended for accurate diagnosis of WG.
    Modern Rheumatology 01/2014; 7(3):183-188. DOI:10.1007/BF03041240 · 2.21 Impact Factor
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    ABSTRACT: We describe a case of severe dermatomyositis (DM) complicated by rhabdomyolysis, acute tubular necrosis, and hemophagocytosis. The case failed to respond to corticosteroids, but showed rapid and significant improvement after the addition of intravenous immunoglobulin (IVIG). While the prognosis of DM is poor when it is complicated by rhabdomyolysis, the early administration of IVIG has the potential to be the cornerstone of its management.
    Modern Rheumatology 11/2013; 25(4). DOI:10.3109/14397595.2013.843753 · 2.21 Impact Factor
  • Hitoshi Kohsaka
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    ABSTRACT: Abstract Steroid myopathy, characterized by muscle atrophy and weakness, is an adverse effect of high-dose steroid therapy. Weakness of proximal muscle that interferes with activities of daily living is a serious problem for patients with steroid myopathy. Here, we outline the pathogenic mechanism, diagnosis, and treatment of steroid myopathy. Recent studies have shown that steroid-mediated induction of ubiquitin ligases (atrogin-1, muscle RING finger-1) and suppression of mammalian/mechanistic target of rapamycin cause an imbalance between anabolism and catabolism of muscle proteins, resulting in muscle atrophy. Despite the progress in understanding the pathogenic mechanism, the diagnosis and treatment of steroid myopathy has not yet been established. Small changes in muscle enzymes, including CK, LDH, and aldolase, make it difficult to define diagnostic criteria. Furthermore, since there is no drug available for treating the disorder, the patients have no opinion except waiting for spontaneous recovery with steroid tapering and exercising. To address these issues, we introduce novel approaches involving branched-chain amino acids that aim at treatment and assessment of steroid myopathy.
    Brain and nerve = Shinkei kenkyū no shinpo 11/2013; 65(11):1375-80.

Publication Stats

2k Citations
514.38 Total Impact Points


  • 1989–2015
    • Tokyo Medical and Dental University
      • • Department of Medicine and Rheumatology
      • • Graduate School of Medical and Dental Sciences
      • • Department of Dermatology
      • • Department of Medicine
      • • Department of Internal Medicine
      • • Medical Research Institute
      Edo, Tōkyō, Japan
    • The University of Tokyo
      Tōkyō, Japan
  • 2014
    • Tazuke Kofukai Medical Research Institute, Kitano Hospital
      Ōsaka, Ōsaka, Japan
  • 2013
    • Saitama Medical University
      • Department of Public Health
      Saitama, Saitama, Japan
  • 2007–2012
    • RIKEN
      Вако, Saitama, Japan
    • Japan Clinical Research Support Unit
      Edo, Tōkyō, Japan
  • 1996
    • National Cheng Kung University
      臺南市, Taiwan, Taiwan
  • 1993–1994
    • University of California, San Diego
      • Department of Medicine
      San Diego, California, United States
    • National University (California)
      San Diego, California, United States