研究者詳細 - 竹内　勤

論文 - 竹内　勤

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Proteomic identification of heterogeneous nuclear ribonucleoprotein K as a novel cold-associated autoantigen in patients with secondary Raynaud's phenomenon

Yang L., Fujimoto M., Murota H., Serada S., Fujimoto M., Honda H., Yamada K., Suzuki K., Nishikawa A., Hosono Y., Yoneda Y., Takehara K., Imura Y., Mimori T., Takeuchi T., Katayama I., Naka T.

Rheumatology (United Kingdom) （Rheumatology (United Kingdom)） 54 （ 2 ） 349 - 358 2015年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1462-0324

© The Author 2014. Objective. The aim of this study was to identify cold-associated autoantibodies in patients with RP secondary to CTDs. Methods. Indirect immunofluorescence staining was performed on non-permeabilized cold-stimulated normal human dermal microvascular endothelial cells (dHMVECs), using patients' sera. Cold-induced alterations in cell surface proteomes were analysed by isobaric tag for relative and absolute quantitation (iTRAQ) analysis. Serological proteome analysis (SERPA) was applied to screen cold-associated autoantigens. The prevalence of the candidate autoantibody was determined by ELISA in 290 patients with RP secondary to CTDs (SSc, SLE or MCTD), 10 patients with primary RP and 27 healthy controls. Results. Enhanced cell surface immunoreactivity was detected in cold-stimulated dHMVECs when incubated with sera from patients with secondary RP. By iTRAQ analysis, many proteins, including heterogeneous nuclear ribonucleoprotein K (hnRNP-K), were found to be increased on the cell surface of dHMVECs after cold stimulation. By the SERPA approach, hnRNP-K was identified as a candidate autoantigen in patients with secondary RP. Cold-induced translocation of hnRNP-K to the cell surface was confirmed by immunoblotting and flow cytometry. By ELISA analysis, patients with secondary RP show a significantly higher prevalence of anti-hnRNP-K autoantibody (30.0%, 61/203) than patients without RP (9.2%, 8/87, P = 0.0001), patients with primary RP (0%, 0/10, P = 0.0314) or healthy controls (0%, 0/27, P = 0.0001). Conclusion. By comprehensive proteomics, we identified hnRNP-K as a novel cold-associated autoantigen in patients with secondary RP. Anti-hnRNP-K autoantibody may potentially serve as a biomarker for RP secondary to various CTDs.

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Elevated levels of pentraxin 3 in systemic sclerosis: Associations with vascular manifestations and defective vasculogenesis

Shirai Y., Okazaki Y., Inoue Y., Tamura Y., Yasuoka H., Takeuchi T., Kuwana M.

Arthritis and Rheumatology （Arthritis and Rheumatology） 67 （ 2 ） 498 - 507 2015年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2326-5191

Copyright © 2015 by the American College of Rheumatology. Objective. To clarify the role of pentraxin 3 (PTX3), a multifunctional pattern recognition protein that can suppress fibroblast growth factor 2 (FGF-2), in systemic sclerosis (SSc)-related vasculopathy. Methods. We assessed 171 SSc patients and 19 age- and sex-matched healthy control subjects. Circulating PTX3 and FGF-2 levels were measured by enzyme immunoassay, and CD34+CD133+CD309+ endothelial progenitor cells (EPCs) were counted by flow cytometry. Correlations between PTX3 and FGF-2 and the presence or future development of vascular manifestations, including digital ulcers and pulmonary arterial hypertension (PAH), were identified by univariate and multivariate analysis. The effect of PTX3 on EPC differentiation was evaluated in proangiogenic cultures of mouse bone marrow cells in combination with colony formation assay. Results. Circulating PTX3 and FGF-2 levels were significantly higher in SSc patients than in healthy control subjects. PTX3 was elevated in SSc patients who had digital ulcers or PAH, while FGF-2 was reduced in SSc patients with PAH. Multivariate analysis identified elevated PTX3 as an independent parameter associated with the presence of digital ulcers and PAH, and PTX3 levels were a useful predictor of future occurrences of digital ulcers. Reduced FGF-2 was independently associated with the presence of PAH. EPC counts were significantly lower in patients with digital ulcers or PAH and correlated negatively with circulating PTX3 concentrations. Finally, PTX3 inhibited EPC differentiation in vitro. Conclusion. In SSc patients, exposure to high concentrations of PTX3 may suppress EPC-mediated vasculogenesis and promote vascular manifestations such as digital ulcers and PAH.

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Obstacles to the implementation of the treat-to-target strategy for rheumatoid arthritis in clinical practice in Japan

Kaneko Y., Koike T., Oda H., Yamamoto K., Miyasaka N., Harigai M., Yamanaka H., Ishiguro N., Tanaka Y., Takeuchi T.

Modern Rheumatology （Modern Rheumatology） 25 （ 1 ） 43 - 49 2015年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2014 Japan College of Rheumatology. Objective. To clarify the obstacles preventing the implementation of the treat-to-target (T2T) strategy for rheumatoid arthritis (RA) in clinical practice. Methods. A total of 301 rheumatologists in Japan completed a questionnaire. In the fi rst section, participants were indirectly questioned on the implementation of basic components of T2T, and in the second section, participants were directly questioned on their level of agreement and application. Results. Although nearly all participants set treatment targets for the majority of RA patients with moderate to high disease activity, the proportion who set clinical remission as their target was 59%, with only 45% of these using composite measures. The proportion of participants who monitored X-rays and Health Assessment Questionnaires for all their patients was 44% and 14%, respectively. The proportion of participants who did not discuss treatment strategies was 44%, with approximately half of these reasoning that this was due to a proportion of patients having a lack of understanding of the treatment strategy or inability to make decisions. When participants were directly questioned, there was a high level of agreement with the T2T recommendations. Conclusion. Although there was a high level of agreement with the T2T recommendations, major obstacles preventing its full implementation still remain.

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Tocilizumab is clinically, functionally, and radiographically effective and safe either with or without low-dose methotrexate in active rheumatoid arthritis patients with inadequate responses to DMARDs and/or TNF inhibitors: A single-center retrospective cohort study (KEIO-TCZ study) at week 52

Izumi K., Kaneko Y., Yasuoka H., Seta N., Kameda H., Kuwana M., Takeuchi T.

Modern Rheumatology （Modern Rheumatology） 25 （ 1 ） 2015年01月

研究論文（国際会議プロシーディングス）, 共著, 査読有り, ISSN 1439-7595

© 2015, Taylor and Francis Ltd. All rights reserved. Objectives. To explore the effectiveness and safety of tocilizumab (TCZ) with or without methotrexate (MTX) in active rheumatoid arthritis (RA) patients showing inadequate responses to DMARDs and/or TNF inhibitors in clinical practice. Methods. We observed consecutive 115 RA patients initiating TCZ treatment in Keio University Hospital, dividing them into two groups with (TCZ + MTX group) or without MTX (TCZ group), and evaluated clinical, functional and structural outcomes besides safety at week 52. Results. Overall mean age, RA duration, and DAS28-ESR were 55.4, 8.4 years, and 5.0, respectively. Proportions of the prior use of TNF inhibitors and concomitant MTX were 45.5% and 57.4%, respectively. Mean dose of concomitant MTX was 8.4 mg/week. Baseline characteristics were comparable between the groups. TCZ improved disease activity measured by DAS28-ESR to 2.1 at week 52 overall, without significant difference between the groups. Clinical (DAS28-ESR < 2.6),functional (HAQ-DI =£0.5), and structural (ATSS<0.5) remission ratesintheTCZgroupand the TCZ + MTX group were 79.1%/63.8% (P = 0.10), 62.8%/54.4% (P = 0.40), and 70.0%/53.8% (P = 0.61), respectively. Retention rates were 81.0% in the TCZ + MTX group and 88.5% in the TCZ group (P = 0.47. The rate of serious adverse events was comparable between the groups. Conclusions. TCZ was clinically, functionally, and radiographically effective and safe either with or without low-dose MTX.

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Efficacy and safety of mavrilimumab in Japanese subjects with rheumatoid arthritis: Findings from a phase iia study

Takeuchi T., Tanaka Y., Close D., Godwood A., Wu C., Saurigny D.

Modern Rheumatology （Modern Rheumatology） 25 （ 1 ） 21 - 30 2015年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2014 Japan College of Rheumatology. Objective. A phase IIa study investigated efficacy and safety/tolerability of ascending doses of mavrilimumab (anti-granulocyte-macrophage colony-stimulating factor receptor [GM-CSFR] α monoclonal antibody) in adult subjects with moderate to severe rheumatoid arthritis from Japan and Europe. Findings from the Japanese population are presented. Methods. Fifty-one subjects received mavrilimumab (10-100 mg) or placebo subcutaneously every other week for 12 weeks, followed by a 12-week follow-up period. The primary endpoint was the proportion of subjects achieving a Disease Activity Score using 28 joints (DAS28)-Creactive protein (CRP) response (decrease > 1.2 from baseline). Secondary endpoints included DAS28-CRP remission, Health Assessment Questionnaire Disability Index (HAQ-DI) and American College of Rheumatology (ACR) response. Results. By Week 12, more mavrilimumab- versus placebo-treated subjects achieved a DAS28-CRP response (50.0% vs. 23.5%, p = 0.081); a signifi cant response was seen in the 30 mg and 100 mg dose groups (both 75.0% vs. 23.5%, p = 0.028). The 100 mg group also demonstrated statistically signifi cant HAQ-DI and ACR20 responses at Week 12. Results were generally consistent between Japanese and European populations. Overall, adverse events (AEs) were mild to moderate in intensity with one serious AE of pneumonia, considered possibly treatment-related. Conclusions. A rapid and clinically meaningful response was seen in subjects treated with GM-CSFR α blockade with mavrilimumab, supporting further investigation of mavrilimumab for the treatment of RA in Japanese subjects.

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Tocilizumab is effective against polymyalgia rheumatica: Experience in 13 intractable cases

Izumi K., Kuda H., Ushikubo M., Kuwana M., Takeuchi T., Oshima H.

RMD Open （RMD Open） 1 （ 1 ） e000162 2015年

研究論文（学術雑誌）, 共著, 査読有り

Polymyalgia rheumatica (PMR) affects older people, and although glucocorticoids are effective in treating PMR, they frequently result in side effects. Therefore, we conducted a retrospective study to assess the effectiveness and safety of tocilizumab as an alternative to glucocorticoids. We included 13 consecutive patients with PMR (11 women and 2 men; median age, 74 years) diagnosed according to Bird's criteria and the 2012 European League Against Rheumatism/ American College of Rheumatology provisional classification criteria. All patients received tocilizumab infusion (8 mg/kg every 4 weeks) at our institutions, between 2008 and 2014, because of PMR relapses (n=12) or insufficient response to initial prednisolone treatment (n=1), without increasing prednisolone dosage. Seven patients were on methotrexate, and all had one or more glucocorticoid-related comorbidities. Administration of tocilizumab significantly improved inflammation and PMR symptoms such as morning stiffness, as well as the Patient-Pain and Patient-Global Assessment visual analogue scales ( p<0.05). Proximal muscle pain disappeared within 8 weeks, on average, and the Health Assessment Questionnaire-Disability Index scores (p=0.098) and concomitant prednisolone doses (p<0.05) decreased at 12 weeks. Severe adverse events were not observed during the mean tocilizumab treatment period of 43.4 weeks. Our findings suggest that tocilizumab is effective and safe for PMR treatment.

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Peripheral blood CD4+CD25+CD127low regulatory T cells are significantly increased by tocilizumab treatment in patients with rheumatoid arthritis: Increase in regulatory T cells correlates with clinical response

Kikuchi J., Hashizume M., Kaneko Y., Yoshimoto K., Nishina N., Takeuchi T.

Arthritis Research and Therapy （Arthritis Research and Therapy） 17 （ 1 ） R10 2015年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1478-6354

© 2015 Kikuchi et al. Tocilizumab (TCZ), an anti-interleukin-6 receptor antibody, is clinically effective against rheumatoid arthritis (RA), and several reports have indicated how TCZ influences a number of mechanisms underlying RA pathogenesis. However, it is still unclear whether TCZ affects inflammatory cells in peripheral blood and whether any such changes are associated with clinical response. We evaluated associations between proportions of subsets of peripheral immune cells and clinical response in patients with RA treated with TCZ. Methods: Thirty-nine consecutive patients with RA who started to receive TCZ as their first biologic between March 2010 and April 2012 were enrolled. The proportions of several subsets of peripheral cells with their levels of expression of differentiation markers, activation markers and costimulatory molecules were measured sequentially from baseline to week 52 by flow cytometry analysis. Results: Clinical Disease Activity Index (CDAI) remission was achieved in 53.8% of patients at week 52 of TCZ therapy. The proportions of CD4+CD25+CD127low regulatory T cells (Treg) and HLA-DR+ activated Treg cells significantly increased with TCZ therapy (P<0.001 and P<0.001, respectively), whereas proportions of CD3+CD4+CXCR3-CCR6+CD161+ T helper 17 cells did not change over the 52weeks. The proportions of CD20+CD27+ memory B cells, HLA-DR+CD14+ and CD69+CD14+ activated monocytes, and CD16+CD14+ monocytes significantly decreased (P<0.001, P<0.001, P<0.001 and P<0.001, respectively). Among them, only the change in Treg cells was inversely correlated with the change in CDAI score (ρ=-0.40, P=0.011). The most dynamic increase in Treg cells was observed in the CDAI remission group (P<0.001). Conclusion: This study demonstrates that TCZ affected proportions of circulating immune cells in patients with RA. The proportion of Treg cells among CD4+ cells correlated well with clinical response.

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Subclinical labial salivary gland involvement in IgG4-related disease affected with vital organs

Akiyama M., Kaneko Y., Yamaoka K., Hayashi Y., Yasuoka H., Suzuki K., Takeuchi T.

Clinical and Experimental Rheumatology 33 （ 6 ） 949 - 950 2015年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0392-856X

Overexpression of CXCR4 on circulating B cells in patients with active systemic lupus erythematosus

Hanaoka H., Okazaki Y., Hashiguchi A., Yasuoka H., Takeuchi T., Kuwana M.

Clinical and Experimental Rheumatology （Clinical and Experimental Rheumatology） 33 （ 6 ） 863 - 870 2015年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0392-856X

© Clinical and Experimental Rheumatology 2015. Objective: To evaluate the roles of circulating B cells in the pathogenic process of systemic lupus erythematosus (SLE) by measuring the expression of chemokines and their receptors. Methods: Peripheral-blood mononuclear cells were obtained from 17 active, 21 inactive SLE patients, and 13 healthy controls. The expression of CXCR4, CXCR5, and CCR7 on CD19+ B cells was determined by flow cytometry, serum concentration of CXCL12 was measured by enzyme-linked immunosorbent assay, and the chemotactic responsiveness of B cells toward CXCL12 was evaluated. B or plasma cells expressing CXCR4 in renal biopsy specimens were detected using immnofluorescent staining. Results: Flow cytometric analysis revealed that expression level of CXCR4 on circulating B cells was significantly higher in patients with active disease than in those with inactive disease or controls. Serum CXCL12 concentration was not different between these groups. In addition, the migratory ability of B cells toward CXCL12 was enhanced in active SLE patients. Finally, CXCR4-expressing B cells were more frequently observed in the renal biopsy specimens of lupus nephritis. Conclusion: Up-regulated CXCR4 expression on circulating B cells in active SLE may enhance their chemotactic response toward CXCL12, which may promote infiltration of these cells into inflamed renal tissue and contribute to the development of SLE.

Biologic-free remission of established rheumatoid arthritis after discontinuation of abatacept: A prospective, multicentre, observational study in Japan

Takeuchi T., Matsubara T., Ohta S., Mukai M., Amano K., Tohma S., Tanaka Y., Yamanaka H., Miyasaka N.

Rheumatology (United Kingdom) （Rheumatology (United Kingdom)） 54 （ 4 ） 683 - 691 2014年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1462-0324

© The Author 2014. Objective. The aim of this study was to determine whether biologic-free remission of RA is possible with discontinuation of abatacept. Methods. Japanese RA patients in 28-joint DAS with CRP (DAS28-CRP) remission (<2.3) after >2 years of abatacept treatment in a phase II study and its long-term extension entered this 52 week, multicentre, non-blinded, prospective, observational study. At enrolment, the patients were offered the option to continue abatacept or not. The primary endpoint was the proportion of patients who remained biologic-free at 52 weeks after discontinuation. Clinical, functional and structural outcomes were compared between those who continued and those who discontinued abatacept. Results. Of 51 patients enrolled, 34 discontinued and 17 continued abatacept treatment. After 52 weeks, 22 of the 34 patients (64.7%) remained biologic-free. Compared with the continuation group, the discontinuation group had a similar remission rate (41.2% vs 64.7%, P = 0.144) although they had a significantly higher mean DAS28-CRP score at week 52 (2.9 vs 2.0, P = 0.012). The two groups were also similar with regard to mean HAQ Disability Index (HAQ-DI) score (0.6 for both, P = 0.920), mean change in total Sharp score (ΔTSS; 0.80 vs 0.32, P = 0.374) and proportion of patients in radiographic remission (ΔTSS≤0.5) at the endpoint (64.3% vs 70.6%, P = 0.752). Those attaining DAS28-CRP<2.3 or<2.7 without abatacept at the endpoint had significantly lower HAQ-DI score and/or CRP at enrolment. Non-serious adverse events occurred in three patients who continued or resumed abatacept. Conclusion. Biologic-free remission of RA is possible in some patients after attaining clinical remission with abatacept. Lower baseline HAQ-DI or CRP may predict maintenance of remission or low disease activity after discontinuation of abatacept.

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Efficacy, safety, pharmacokinetics and immunogenicity of abatacept administered subcutaneously or intravenously in Japanese patients with rheumatoid arthritis and inadequate response to methotrexate: A Phase II/III, randomized study

Iwahashi M., Inoue H., Matsubara T., Tanaka T., Amano K., Kanamono T., Nakano T., Uchimura S., Izumihara T., Yamazaki A., Karyekar C., Takeuchi T.

Modern Rheumatology （Modern Rheumatology） 24 （ 6 ） 885 - 891 2014年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2014 Japan College of Rheumatology. Objective. To evaluate efficacy and safety of subcutaneous (SC) and intravenous (IV) abatacept and background methotrexate (MTX) in Japanese patients with rheumatoid arthritis (RA) and inadequate response to MTX (MTX-IR). Methods. Double-dummy, double-blind study (NCT01001832); 118 adults with ≥ 10 swollen joints, ≥ 12 tender joints and C-reactive protein (CRP) ≥ 0.8 mg/dL randomized 1:1 to SC abatacept (125 mg weekly) with IV loading (~ 10 mg/kg on Day 1), or IV abatacept (~ 10 mg/kg monthly) for 169 days, both also receiving MTX (6-8 mg/week). Primary endpoint was Day 169 American College of Rheumatology (ACR)20 response; other efficacy endpoints, safety and immunogenicity were assessed. Results. Similar proportions of patients achieved ACR20 responses at Day 169 with SC (91.5% [95% CI 81.3, 97.2]) and IV abatacept (83.1% [71.0, 91.6]). ACR50/70 responses, adjusted mean changes from baseline in Health Assessment Questionnaire-Disability Index scores and remission rates (28-joint Disease Activity Score [CRP] < 2.6) were also comparable between groups. Serious adverse event frequencies (5.1% vs. 3.4%) were similar with both formulations. One patient per group tested seropositive for immunogenicity. Weekly SC abatacept dosing achieved mean serum concentrations > 10 μ g/mL (minimum therapeutic target). Conclusions. SC abatacept demonstrated comparable efficacy and safety to IV abatacept, with low immunogenicity rates, in MTX-IR Japanese patients with RA.

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111th Scientific Meeting of the Japanese Society of Internal Medicine: Educational Lecture: 14. Treat to target strategy in rheumatoid arthritis

Takeuchi T., Kaneko Y.

Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine （Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine） 103 （ 9 ） 2321 - 2327 2014年09月

研究論文（学術雑誌）, 査読有り, ISSN 00215384

Early response to certolizumab pegol predicts long-term outcomes in patients with active rheumatoid arthritis: Results from the Japanese studies

Takeuchi T., Yamamoto K., Yamanaka H., Ishiguro N., Tanaka Y., Eguchi K., Watanabe A., Origasa H., Shoji T., Miyasaka N., Koike T.

Modern Rheumatology （Modern Rheumatology） 25 （ 1 ） 11 - 20 2014年05月

研究論文（学術雑誌）, 査読有り, ISSN 14397595

© 2014 Japan College of Rheumatology. Objectives. A post-hoc analysis was performed to determine the relationship between the timing and magnitude of DAS28(ESR) response and long term outcomes in Japanese patients after 1 year of CZP treatment. Methods. Our analysis included 82 J-RAPID trial patients treated with CZP 200 mg and methotrexate, and 116 HIKARI trial patients treated with CZP 200 mg alone or with disease-modifying agents other than methotrexate. Remission rates and changes in mTSS at year 1 were compared to the DAS28(ESR) response at week 12 of CZP treatment. Results. After 1 year of treatment, remission was achieved in 41.3% of the J-RAPID and 34.9% of the HIKARI patients with a week 12 DAS28(ESR) response of ≥ 1.2. In comparison, patients with a DAS28(ESR) response of ≥ 1.2 at week 12 only had a ≥ 7% probability of achieving remission and displayed higher change in mTSS after 1-year treatment. Conclusions. The likelihood of remission and extent of radiographic progression after 1 year was associated with the week 12 DAS28(ESR) response. The DAS28(ESR) response at 12 weeks could be benefi cial for identifying patients that are unlikely to respond to prolonged CZP treatment.

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Adalimumab, a human anti-TNF monoclonal antibody, outcome study for the prevention of joint damage in Japanese patients with early rheumatoid arthritis: The HOPEFUL 1 study

Takeuchi T., Yamanaka H., Ishiguro N., Miyasaka N., Mukai M., Matsubara T., Uchida S., Akama H., Kupper H., Arora V., Tanaka Y.

Annals of the Rheumatic Diseases （Annals of the Rheumatic Diseases） 73 （ 3 ） 536 - 543 2014年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

Objectives To evaluate the efficacy and safety of adalimumab+methotrexate (MTX) in Japanese patients with early rheumatoid arthritis (RA) who had not previously received MTX or biologics. Methods This randomised, double-blind, placebo-controlled, multicentre study evaluated adalimumab 40 mg every other week+MTX 6-8 mg every week versus MTX 6-8 mg every week alone for 26 weeks in patients with RA (≤2-year duration). The primary endpoint was inhibition of radiographic progression (change (Δ) from baseline in modified total Sharp score (mTSS)) at week 26. Results A total of 171 patients received adalimumab+MTX (mean dose, 6.2±0.8 mg/week) and 163 patients received MTX alone (mean dose, 6.6±0.6 mg/week, p<0.001). The mean RA duration was 0.3 years and 315 (94.3%) had high disease activity (DAS28>5.1). Adalimumab+MTX significantly inhibited radiographic progression at week 26 versus MTX alone (ΔmTSS, 1.5±6.1 vs 2.4±3.2, respectively; p<0.001). Significantly more patients in the adalimumab+MTX group (62.0%) did not show radiographic progression (ΔmTSS≤0.5) versus the MTX alone group (35.4%; p<0.001). Patients treated with adalimumab+MTX were significantly more likely to achieve American College of Rheumatology responses and achieve clinical remission, using various definitions, at 26 weeks versus MTX alone. Combination therapy was well tolerated, and no new safety signals were observed. Conclusions Adalimumab in combination with low-dose MTX was well tolerated and efficacious in suppressing radiographic progression and improving clinical outcomes in Japanese patients with early RA and high disease activity.

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Overview of lupus nephritis management guidelines and perspective from Asia

Mok Chi Chiu, Yap Desmond Y H, Navarra Sandra V., Liu Zhi Hong, Zhao Ming Hui, Lu Liangjing, Takeuchi Tsutomu, Avihingsanon Yingyos, Yu Xue Qing, Lapid Elizabeth A., Lugue-Lizardo Lenrore R., Sumethkul Vasant, Shen Nan, Chen Shun Le, Chan Tak Mao

Nephrology 19 （ 1 ） 11 - 20 2014年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1320-5358

Lupus nephritis (LN) is a common and important manifestation of systemic lupus erythematosus (SLE). Evidence suggests higher rates of lupus renal involvement in Asian populations, and maybe more severe nephritis, compared with other racial or ethnic groups. The management of LN has evolved considerably over the past three decades, based on observations from clinical studies that investigated different immunosuppressive agents including corticosteroids, cyclophosphamide, azathioprine, mycophenolic acid, calcineurin inhibitors and novel biologic therapies. This is accompanied by improvements in both the short-term treatment response rate and long-term renal function preservation. Treatment guidelines for LN have recently been issued by rheumatology and nephrology communities in U.S.A. and Europe. In view of the racial difference in disease manifestation and response to therapy, and the substantial disease burden in Asia, a panel of 15 nephrologists and rheumatologists from different Asian regions with extensive experience in lupus nephritis - the Steering Group for the Asian Lupus Nephritis Network (ALNN) - met and discussed the management of lupus nephritis in Asian patients. The group has also reviewed and deliberated on the recently published recommendations from other parts of the world. This manuscript summarizes the discussions by the group and presents consensus views on the clinical management and treatment of adult Asian patients with LN, taking into account both the available evidence and expert opinion in areas where evidence remains to be sought. © 2013 The Authors. Nephrology © 2013 Asian Pacific Society of Nephrology.

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The multicenter study of a new assay for simultaneous detection of multiple anti-aminoacyl-tRNA synthetases in myositis and interstitial pneumonia

竹内勤

PLoS ONE （PLoS ONE） 9 （ 1 ） 89 - 90 2014年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1932-6203

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. © 2014 Nakashima et al.

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Effectiveness and safety of tocilizumab: Postmarketing surveillance of 7901 patients with rheumatoid arthritis in Japan

Koike T., Harigai M., Inokuma S., Ishiguro N., Ryu J., Takeuchi T., Takei S., Tanaka Y., Sano Y., Yaguramaki H., Yamanaka H.

Journal of Rheumatology （Journal of Rheumatology） 41 （ 1 ） 15 - 23 2014年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

Objective. An all-patient postmarketing surveillance program was conducted to evaluate the safety and effectiveness of tocilizumab (TCZ) for rheumatoid arthritis (RA) in the real-world clinical setting in Japan. Methods. Patients received 8 mg/kg TCZ every 4 weeks and were observed for 28 weeks. Data were collected on patient characteristics, and drug safety and effectiveness. Results. A total of 7901 patients were enrolled. Percentages of total and serious adverse events (AE) were 43.9% and 9.6%, respectively. The most common serious AE were infections (3.8%). Logistic regression analysis identified the following risk factors for the development of serious infection: age ≥ 65 years, disease duration ≥ 10 years, previous or concurrent respiratory disease, and concomitant corticosteroid dose > 5 mg/day (prednisolone equivalent). The incidence rate of serious infections in patients with ≥ 3 risk factors was 11.2%, compared with 1.2% for patients without risk factors. The Week 28 rates of 28-joint Disease Activity Score-erythrocyte sedimentation rate remission, Boolean remission, and European League Against Rheumatism (EULAR) Good Response were 47.6%, 15.1%, and 59.4%, respectively. Contributing factors for effectiveness were body weight ≥ 40 kg, less advanced RA, no previous biologics, no concomitant corticosteroids or nonsteroidal antiinflammatory drugs, and low disease activity at baseline. From the benefit-risk balance analysis, patients with a high probability of remission and a low probability of developing serious infection were most likely to have less advanced RA and to have not received biologics previously. Conclusion. These data confirm the safety and effectiveness of TCZ in patients with RA in the real-world clinical setting in Japan and identify factors that contribute to the successful use of TCZ for RA. The Journal of Rheumatology Copyright © 2014. All rights reserved.

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Addition of another disease-modifying anti-rheumatic drug to methotrexate reduces the flare rate within 2 years after infliximab discontinuation in patients with rheumatoid arthritis: An open, randomized, controlled trial

Kurasawa T., Nagasawa H., Kishimoto M., Amano K., Takeuchi T., Kameda H.

Modern Rheumatology （Modern Rheumatology） 24 （ 4 ） 561 - 566 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objectives. We examined whether the addition of another conventional disease-modifying anti-rheumatic drugs (DMARDs) to methotrexate (MTX) upon infliximab (IFX) discontinuation in well-controlled rheumatoid arthritis (RA) patients could suppress subsequent disease flare. Methods. RA patients maintaining DAS28-CRP (Disease Activity Score of 28 joints with C-reactive protein) scores < 2.6 for ≥ 6 months with IFX were randomized either to receive addition of bucillamine (BUC) to MTX (BUC + MTX group; n = 24) or not (MTX group; n = 31) upon discontinuing IFX. The primary endpoint was the flare rate within 2 years of IFX discontinuation. Results. Six patients discontinuing MTX during the study were excluded from analyses. Seventeen patients (63.0%) experienced flares in the MTX group, which was significantly reduced in the BUC + MTX group (31.8%; p = 0.045). Further, the flare rates differed significantly between remission and non-remission by a Boolean definition upon IFX discontinuation in the MTX group (40.0% vs. 91.7%, respectively; p = 0.014), but they were comparable in the BUC + MTX group. BUC treatment was interrupted in seven patients due to rash, proteinuria and incompliance. Conclusions. DMARDs combination therapy may be a better treatment strategy than MTX monotherapy for maintaining RA control after successful discontinuation of biological agents. © 2014 The Authors.

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A paradigm shift in rheumatoid arthritis over the past decade

Kaneko Y., Takeuchi T.

Internal Medicine （Internal Medicine） 53 （ 17 ） 1895 - 1903 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0918-2918

© 2014 The Japanese Society of Internal Medicine. Recent advances have improved our understanding of the pathogenesis of rheumatoid arthritis (RA), and the development of new therapeutics, including biological agents, have thus made it possible to strive for remission as a primary goal. Biological agents targeting a specific molecule have powerful functional capabilities, and the introduction of biological therapies has brought about revolutionary progress in RA management, culminating in a paradigm shift. There is clear evidence that a delay in treatment initiation and poor control of disease activity are associated with joint damage progression, so treatment should be started immediately after the diagnosis of RA and adapted according to disease activity as assessed by validated composite measures. In this review, we will summarize the changes in the classification and remission criteria and describe the clinical efficacies of biological agents in RA. We also discuss new promising therapies and propose future perspectives in the rheumatology field.

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Post-marketing surveillance of the safety and effectiveness of tacrolimus in 3,267 Japanese patients with rheumatoid arthritis

Takeuchi Tsutomu, Kawai Shinichi, Yamamoto Kazuhiko, Harigai Masayoshi, Ishida Kota, Miyasaka Nobuyuki

Modern Rheumatology 24 （ 1 ） 8 - 16 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objectives A post-marketing surveillance (PMS) program was implemented to assess the safety and effectiveness of tacrolimus (TAC) in Japanese rheumatoid arthritis (RA) patients and to identify risk factors related to adverse drug reactions (ADRs). Methods Patients were registered centrally and monitored for all adverse events (AEs) for 24 weeks. Effectiveness was evaluated using the Disease Activity Score 28-CRP (DAS28-CRP). Results Data from 3,172 patients (mean age 62.2 years) were evaluated in the safety analysis. Of the safety population, 78.5 %were female and 25.9 % were in Steinbrocker's functional class 3 or 4. TAC was prescribed as monotherapy in 52.5 % and the most common concomitant disease modifying antirheumatic drug (DMARD) was methotrexate, used in 28.9 % of the patients. The incidence of AEs, serious AEs (SAEs), ADRs and serious ADRs were 41.2, 6.4, 36.0, and 4.9 %, respectively. The most frequent serious ADR category was infections and infestations. Age ≥ 65 years, concurrent renal dysfunction, and concurrent diabetes mellitus were identified as significant risk factors for ADR. Based on EULAR response criteria, 65.4 % of the patients showed moderate or good response. Conclusions The results demonstrate that TAC is well tolerated by Japanese patients with active RA, including those receiving concomitant methotrexate, in the real world. © 2013 Japan College of Rheumatology.

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