研究者詳細 - 竹内　勤

論文 - 竹内　勤

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Efficacy of denosumab with regard to bone destruction in prognostic subgroups of Japanese rheumatoid arthritis patients from the phase II DRIVE study.

Ishiguro N, Tanaka Y, Yamanaka H, Yoneda T, Ohira T, Okubo N, Genant HK, van der Heijde D, Takeuchi T

Rheumatology (Oxford, England) 2019年01月

研究論文（学術雑誌）, 査読有り, ISSN 1462-0324

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Safety Profile of Baricitinib in Patients with Active Rheumatoid Arthritis with over 2 Years Median Time in Treatment

Smolen Josef S., Genovese Mark C., Takeuchi Tsutomu, Hyslop David L., Macias William L., Rooney Terence, Chen Lei, Dickson Christina L., Camp Jennifer Riddle, Cardillo Tracy E., Ishii Taeko, Winthrop Kevin L.

JOURNAL OF RHEUMATOLOGY 46 （ 1 ） 7 - 18 2019年01月

研究論文（学術雑誌）, 査読有り, ISSN 0315-162X

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Initial presentation determines clinical entity in patients with anti-centromere antibody positivity

Tsukamoto M., Suzuki K., Takeuchi T.

International Journal of Rheumatic Diseases （International Journal of Rheumatic Diseases） 22 （ 1 ） 103 - 107 2019年01月

研究論文（学術雑誌）, 査読有り, ISSN 17561841

© 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd Aim: Anti-centromere antibody (ACA) is often detected in patients with autoimmune diseases, including limited cutaneous systemic sclerosis (SSc), Sjögren's syndrome (SS), and primary biliary cholangitis (PBC). The association between autoimmune disease and ACA positivity remains unclear. We sought to clarify the clinical features of ACA-positive patients and their association with autoantibodies. Method: A total of 309 cases of a discrete-speckled pattern anti-nuclear antibody (ANA) test and/or positive ACA who visited our department were retrospectively enrolled. Clinical and immunological data were collected and statistically analyzed. Result: A proportion of second and/or third ANA patterns were speckled (16%), homogenous (7%), cytoplasmic (3%) and/or nucleolar (3%). Of the 309 patients, 186 had Raynaud's phenomenon, 149 had sclerodactyly, and 162 had oral and/or ocular dryness. A total of 214 patients were classified into 17 autoimmune diseases based on their symptoms at the initial visit, while the other 95 patients did not meet any criteria. Most of the 214 patients were diagnosed with SSc and/or SS; 25 and 22 additional patients were diagnosed with rheumatoid arthritis and PBC, respectively. Higher titers of immunoglobulins were observed in patients diagnosed with autoimmune disease compared to patients without a diagnosis. The mean observation period was 80 months. Three additional patients received interim diagnoses based on new symptoms or organ involvement. In the other patients, the diagnosis made at the first visit was not changed over the observation period. Conclusion: Our study confirmed that many ACA-positive cases can be classified into an autoimmune disease type on presentation.

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Ten-year observation of patients with primary Sjögren's syndrome: Initial presenting characteristics and the associated outcomes.

Tsukamoto M, Suzuki K, Takeuchi T

International journal of rheumatic diseases 2018年12月

研究論文（学術雑誌）, 査読有り, ISSN 1756-1841

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Response to: 'Some concerns from Turkey' by Bilgin et al.

Kaneko Y, Kameda H, Ikeda K, Ishii T, Murakami K, Takamatsu H, Tanaka Y, Abe T, Takeuchi T

Annals of the rheumatic diseases 2018年12月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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Tocilizumab in patients with adult-onset still's disease refractory to glucocorticoid treatment

Kaneko Yuko, Kameda Hideto, Ikeda Kei, Ishii Tomonoti, Murakami Kosaku, Takamatsu Hyota, Tanaka Yoshiya, Abe Takayuki, Takeuchi Tsutomu

Annals of the rheumatic diseases 77 1270 - 1279 2018年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

Objective: To evaluate the efficacy and safety of tocilizumab, an interleukin-6 receptor antibody, in patients with adult-onset Still's disease. Methods: In this double-blind, randomised, placebo-controlled phase III trial, 27 patients with adult-onset Still's disease refractory to glucocorticoids were randomised to tocilizumab at a dose of 8 mg/kg or placebo given intravenously every 2 weeks during the 12-week, double-blind phase. Patients received open-label tocilizumab for 40 weeks subsequently. The primary outcome was American College of Rheumatology (ACR) 50 response at week 4. The secondary outcomes included ACR 20/50/70, systemic feature score, glucocorticoid dose and adverse events at each point. Results: In the full analysis set, ACR50 response at week 4 was achieved in 61.5% (95% CI 31.6 to 86.1) in the tocilizumab group and 30.8% (95% CI 9.1 to 61.4) in the placebo group (p=0.24). The least squares means for change in systemic feature score at week 12 were -4.1 in the tocilizumab group and -2.3 in the placebo group (p=0.003). The dose of glucocorticoids at week 12 decreased by 46.2% in the tocilizumab group and 21.0% in the placebo group (p=0.017). At week 52, the rates of ACR20, ACR50 and ACR70 were 84.6%, 84.6% and 61.5%, respectively, in both groups. Serious adverse events in all participants who received one dose of tocilizumab were infections, aseptic necrosis in the hips, exacerbation of adult-onset Still's disease, drug eruption and anaphylactic shock. Conclusion: The study suggests that tocilizumab is effective in adult-onset Still's disease, although the primary endpoint was not met and solid conclusion was not drawn.

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Multi-omics monitoring of drug response in rheumatoid arthritis in pursuit of molecular remission

Tasaki S., Suzuki K., Kassai Y., Takeshita M., Murota A., Kondo Y., Ando T., Nakayama Y., Okuzono Y., Takiguchi M., Kurisu R., Miyazaki T., Yoshimoto K., Yasuoka H., Yamaoka K., Morita R., Yoshimura A., Toyoshiba H., Takeuchi T.

Nature Communications （Nature Communications） 9 （ 1 ） 2755 2018年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2041-1723

© 2018 The Author(s). Sustained clinical remission (CR) without drug treatment has not been achieved in patients with rheumatoid arthritis (RA). This implies a substantial difference between CR and the healthy state, but it has yet to be quantified. We report a longitudinal monitoring of the drug response at multi-omics levels in the peripheral blood of patients with RA. Our data reveal that drug treatments alter the molecular profile closer to that of HCs at the transcriptome, serum proteome, and immunophenotype level. Patient follow-up suggests that the molecular profile after drug treatments is associated with long-term stable CR. In addition, we identify molecular signatures that are resistant to drug treatments. These signatures are associated with RA independently of known disease severity indexes and are largely explained by the imbalance of neutrophils, monocytes, and lymphocytes. This high-dimensional phenotyping provides a quantitative measure of molecular remission and illustrates a multi-omics approach to understanding drug response.

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IL-6, IL-17 and Stat3 are required for auto-inflammatory syndrome development in mouse

Oike T., Kanagawa H., Sato Y., Kobayashi T., Nakatsukasa H., Miyamoto K., Nakamura S., Kaneko Y., Kobayashi S., Harato K., Yoshimura A., Iwakura Y., Takeuchi T., Matsumoto M., Nakamura M., Niki Y., Miyamoto T.

Scientific Reports （Scientific Reports） 8 （ 1 ） 15783 2018年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2045-2322

© 2018, The Author(s). Auto-inflammatory syndrome, a condition clinically distinct from rheumatoid arthritis, is characterized by systemic inflammation in tissues such as major joints, skin, and internal organs. Autonomous innate-immune activation is thought to promote this inflammation, but underlying pathological mechanisms have not been clarified nor are treatment strategies established. Here, we newly established a mouse model in which IL-1 signaling is conditionally activated in adult mice (hIL-1 cTg) and observed phenotypes similar to those seen in auto-inflammatory syndrome patients. In serum of hIL-1 cTg mice, IL-6 and IL-17 levels significantly increased, and signal transducer and activator of transcription 3 (Stat3) was activated in joints. When we crossed hIL-1 cTg with either IL-6- or IL-17-deficient mice or with Stat3 conditional knockout mice, phenotypes seen in hIL-1 cTg mice were significantly ameliorated. Thus, IL-6, IL-17 and Stat3 all represent potential therapeutic targets for this syndrome.

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Tocilizumab in patients with adult-onset still's disease refractory to glucocorticoid treatment: A randomised, double-blind, placebo-controlled phase III trial

Kaneko Y., Kameda H., Ikeda K., Ishii T., Murakami K., Takamatsu H., Tanaka Y., Abe T., Takeuchi T.

Annals of the Rheumatic Diseases （Annals of the Rheumatic Diseases） 77 （ 12 ） 1720 - 1729 2018年12月

研究論文（学術雑誌）, 査読有り, ISSN 00034967

© © Author(s) (or their employer(s)) 2018. Objective To evaluate the efficacy and safety of tocilizumab, an interleukin-6 receptor antibody, in patients with adult-onset Still's disease. Methods In this double-blind, randomised, placebo-controlled phase III trial, 27 patients with adult-onset Still's disease refractory to glucocorticoids were randomised to tocilizumab at a dose of 8 mg/kg or placebo given intravenously every 2 weeks during the 12-week, double-blind phase. Patients received open-label tocilizumab for 40 weeks subsequently. The primary outcome was American College of Rheumatology (ACR) 50 response at week 4. The secondary outcomes included ACR 20/50/70, systemic feature score, glucocorticoid dose and adverse events at each point. Results In the full analysis set, ACR50 response at week 4 was achieved in 61.5% (95% CI 31.6 to 86.1) in the tocilizumab group and 30.8% (95% CI 9.1 to 61.4) in the placebo group (p=0.24). The least squares means for change in systemic feature score at week 12 were -4.1 in the tocilizumab group and -2.3 in the placebo group (p=0.003). The dose of glucocorticoids at week 12 decreased by 46.2% in the tocilizumab group and 21.0% in the placebo group (p=0.017). At week 52, the rates of ACR20, ACR50 and ACR70 were 84.6%, 84.6% and 61.5%, respectively, in both groups. Serious adverse events in all participants who received one dose of tocilizumab were infections, aseptic necrosis in the hips, exacerbation of adult-onset Still's disease, drug eruption and anaphylactic shock. Conclusion The study suggests that tocilizumab is effective in adult-onset Still's disease, although the primary endpoint was not met and solid conclusion was not drawn.

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Abatacept in combination with methotrexate in Japanese biologic-naive patients with active rheumatoid arthritis: A randomised placebocontrolled phase IV study

Matsubara T., Inoue H., Nakajima T., Tanimura K., Sagawa A., Sato Y., Osano K., Nagano S., Ueki Y., Hanyu T., Hashizume K., Amano N., Tanaka Y., Takeuchi T.

RMD Open （RMD Open） 4 （ 2 ） e000813 2018年12月

研究論文（学術雑誌）, 査読有り, ISSN 2056-5933

© Author(s) (or their employer(s)) 2018. Objectives: To evaluate efficacy and safety of abatacept+methotrexate (MTX) in biologic-naive, anticitrullinated protein antibody (ACPA)-positive Japanese patients with active rheumatoid arthritis (RA) and early erosion versus placebo+MTX. Methods: In this phase IV, multicentre, double-blind study (NCT01758198), patients were randomised (1:1) to receive intravenous abatacept (~10 mg/kg) or placebo, plus MTX (≥6 mg/week). Primary efficacy objectives were to compare American College of Rheumatology 20 (ACR20) response rates at week 16 and mean change from baseline in van der Heijde-modified total Sharp score (vdH-mTSS) at week 24 between abatacept+MTX and placebo+MTX groups. Results: Overall, 203 and 202 patients received abatacept+MTX and placebo+MTX, respectively. At week 16, ACR20 response rates were higher in the abatacept (75.4%) versus placebo group (27.7%; p<0.001). Mean change from baseline in vdH-mTSS at week 24 was 0.84 in the abatacept and 1.26 in the placebo group (p=0.017). Radiographic nonprogression rates (change in vdH-mTSS≤smallest detectable change (2.4)) were 88.1% and 75.4% in abatacept and placebo groups, respectively. Adjusted mean change from baseline in Disease Activity Score 28 (C-reactive protein) (DAS28 (CRP)) at week 16 demonstrated a numerically greater reduction in the abatacept versus placebo group. Proportions of patients with DAS28 (CRP), Simplified Disease Activity Index and Clinical Disease Activity Index remission up to week 52 were higher in the abatacept versus placebo group. The abatacept safety profile was consistent with previous observations. Conclusions: C ompared with MTX alone, abatacept+MTX improved clinical symptoms and inhibited structural damage progression in ACPA-positive, Japanese patients with RA, early erosion and inadequate response to MTX.

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Clinical and Immunological Features of Anti-centromere Antibody-Positive Primary Sjogren's Syndrome

Tsukamoto Masako, Suzuki Katsuya, Takeuchi Tsutomu

RHEUMATOLOGY AND THERAPY 5 （ 2 ） 499 - 505 2018年12月

研究論文（学術雑誌）, 査読有り, ISSN 2198-6576

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Clinical and Immunological Features of Anti-centromere Antibody-Positive Primary Sjögren's Syndrome.

Tsukamoto M, Suzuki K, Takeuchi T

Rheumatology and therapy 5 （ 2 ） 499 - 505 2018年12月

研究論文（学術雑誌）, 査読有り, ISSN 2198-6576

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Phenotype of Platelets Are Altered and Activated in Circulation of Patients with Systemic Sclerosis

Yasuoka Hidekata, Sakata Komei, Yoshimoto Keiko, Takeuchi Tsutomu

BLOOD 132 2018年11月

研究論文（学術雑誌）, 査読有り, ISSN 0006-4971

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Successful rituximab treatment of granulomatosis with polyangiitis with cranial neuropathies

Nakazawa Maho, Suzuki Katsuya, Yasuoka Hidekata, Yamaoka Kunihiro, Takeuchi Tsutomu

INFLAMMATION AND REGENERATION 38 20 2018年11月

研究論文（学術雑誌）, 査読有り, ISSN 1880-8190

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Response to e-letter: 'Tocilizumab in patients with adult-onset Still's disease refractory to glucocorticoid treatment' by Lee.

Kaneko Y, Kameda H, Ikeda K, Ishii T, Murakami K, Takamatsu H, Tanaka Y, Abe T, Takeuchi T

Annals of the rheumatic diseases 2018年11月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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Determinants of Patient’s Global Assessment of Disease Activity and Physician’s Global Assessment of Disease Activity in patients with rheumatoid arthritis: A post hoc analysis of overall and Japanese results from phase 3 clinical trials

Kaneko Y., Takeuchi T., Cai Z., Sato M., Awakura K., Gaich C., Zhu B., Guo J., Tanaka Y.

Modern Rheumatology （Modern Rheumatology） 28 （ 6 ） 960 - 967 2018年11月

研究論文（学術雑誌）, 査読有り, ISSN 14397595

© 2018, © 2018 Japan College of Rheumatology. Published by Informa UK Limited, trading as Taylor & Francis Group. Objectives: To assess the determinants of Patient’s Global Assessment of Disease Activity (PtGA) and Physician’s Global Assessment of Disease Activity (PhGA) in overall and Japanese patients with rheumatoid arthritis (RA) from two large randomized controlled trials. Methods:Post hoc analysis of overall and Japanese RA patients who had previous inadequate responses to methotrexate or who had no/minimal previous disease-modifying antirheumatic drug treatment. We examined correlations between PtGA/PhGA and tender joint count in 28 joints (TJC28), swollen joint count in 28 joints (SJC28), inflammatory markers, pain visual analog scale (VAS), and other patient-reported outcomes at baseline, Week 12, and Week 24. Determinants of PtGA/PhGA were identified. Results: In overall populations, pain VAS was the main determinant of PtGA, whereas TJC28 was the main determinant of PhGA in both studies. In Japanese populations, consistent with overall populations, pain VAS was the main determinant of PtGA in both studies; in contrast to overall populations, pain VAS and SJC28/TJC28 played an important role in PhGA. Conclusion: Pain was the most important determinant of PtGA, whereas determinants of PhGA varied between populations/studies and were mostly explained by pain/joint counts. Physicians should be aware of patients’ perceptions of disease activity when performing assessments/prescribing treatments.

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Efficacy and safety of sirukumab in Japanese patients with moderate to severe rheumatoid arthritis inadequately controlled by disease modifying anti-rheumatic drugs: Subgroup analysis of a phase 3 study

Takeuchi T., Tanaka Y., Yamanaka H., Harigai M., Nakano T., Akagi K., Ukyo Y., Hsu B.

Modern Rheumatology （Modern Rheumatology） 28 （ 6 ） 941 - 949 2018年11月

研究論文（学術雑誌）, 査読有り, ISSN 14397595

© 2018, © 2018 Japan College of Rheumatology. Published by Informa UK Limited, trading as Taylor & Francis Group. Objective: To evaluate the efficacy and safety of sirukumab in Japanese patients with active rheumatoid arthritis (RA) uncontrolled by disease-modifying antirheumatic drugs. Methods: This subgroup analysis based on a double-blind, placebo-controlled, 52-week phase 3 study (SIRROUND-D) assessed American College of Rheumatology (ACR) 20 response at week 16 and van der Heijde-modified Sharp score (vdH-S) at week 52 (coprimary endpoints). Results: A total of 168 (Japanese)/1670 patients received sirukumab 50 mg/4 weeks (q4w, n = 58), 100 mg/every 2 weeks (q2w, n = 54), or placebo (n = 56) subcutaneously. Significantly more patients achieved ACR20 response at week 16 with sirukumab (50 mg q4w: 69.0%; 100mg q2w: 66.7%) vs. placebo (21.4%; p <.001). Median change from baseline in total vdH-S score at week 52 was significantly lower with sirukumab (50 mg q4w: 0.3, p =.024; 100 mg q2w: 0.0, p =.002) vs. placebo (1.3). Sirukumab consistently showed greater improvements in secondary endpoints at weeks 24 and 52. Nasopharyngitis, elevated liver enzymes, injection site erythema and upper respiratory tract infections were the common treatment-emergent adverse events (TEAEs). Incidences of TEAEs and serious AEs were consistent between sirukumab groups through week 52. Conclusion: Sirukumab showed clinically meaningful improvements consistent with significant improvements in the global study. No new safety signals were observed.

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Investigating sirukumab for rheumatoid arthritis: 2-year results from the phase III SIRROUND-D study

Thorne C., Takeuchi T., Karpouzas G., Sheng S., Kurrasch R., Fei K., Hsu B.

RMD Open （RMD Open） 4 （ 2 ） e000731 2018年11月

研究論文（学術雑誌）, 査読有り, ISSN 2056-5933

© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. Objectives The phase III, multicentre, randomised, double-blind, placebo-controlled, parallel-group SIRROUND-D study evaluated long-term efficacy and safety of the interleukin (IL)-6 inhibitor, sirukumab, in patients with active rheumatoid arthritis (RA) refractory to disease-modifying antirheumatic drugs (DMARDs). Methods Patients were randomised 1:1:1 to sirukumab 100mg every 2 weeks (q2w), 50mg every 4 weeks or placebo q2w subcutaneously. Patients initially randomised to placebo were rerandomised at Weeks 18, 40 or 52 to one of the sirukumab groups until Week 104. Results Of 1670 randomised patients, 1402 were included in the full analysis set and 1269 in the radiographic analysis set at Week 104. American College of Rheumatology scores, Disease Activity Score based on C-reactive protein, Clinical Disease Activity Index and clinically meaningful improvements in patient-reported outcomes were sustained at Week 104 among patients initially randomised to sirukumab. Placebo patients subsequently rerandomised to sirukumab showed clinical improvements at Week 104 that were comparable to results among patients initially randomised to sirukumab. Radiographic progression from Week 52 to Week 104 was comparable between all groups whether initially randomised to sirukumab or subsequently rerandomised to sirukumab from placebo. No new safety signals were identified in the extended exposure period compared with the initial 52 weeks of treatment. Conclusions Sirukumab treatment resulted in sustained reductions in clinical signs and symptoms and minimal progression in radiographic damage over 2 years among patients with RA refractory to DMARDs. The safety profile of sirukumab was as expected for an anti-IL-6 agent, with no new signals reported.

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Beneficial effects of Denosumab on bone loss and bone erosion from results of long-term treatment in the phase 3, DESIRABLE study in patients with rheumatoid arthritis (RA) on background csDMARDs

Tanaka Yoshiya, Soen Satoshi, Yamanaka Hisashi, Yoneda Toshiyuki, Tanaka Sakae, Nitta Takaya, Okubo Naoki, Genant Harry, Van der Heijde Desiree, Takeuchi Tsutomu

JOURNAL OF BONE AND MINERAL RESEARCH 33 90 - 90 2018年11月

研究論文（学術雑誌）, 査読有り, ISSN 0884-0431

Safety and effectiveness of abatacept in Japanese non-elderly and elderly patients with rheumatoid arthritis in an all-cases post-marketing surveillance.

Harigai M, Ishiguro N, Inokuma S, Mimori T, Ryu J, Takei S, Takeuchi T, Tanaka Y, Takasaki Y, Yamanaka H, Yoshizawa Y, Chinen I, Nakao T, Koike T

Modern rheumatology 1 - 9 2018年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objectives: To investigate the safety, effectiveness, and risk-benefit balance of intravenous abatacept (ABA) in non-elderly (<65 years: NEG) and elderly (≥65 years: EG) rheumatoid arthritis patients. Methods: This sub-analysis of an all-cases postmarketing surveillance in Japan assessed safety in all enrolled patients and effectiveness in those with Disease Activity Score 28 based on C-reactive protein (DAS28-CRP) measurements at ≥2 time points including baseline. Risk-benefit was evaluated based on infections and DAS28-CRP improvement >1.2. Results: The NEG and EG of the safety analysis set comprised 2,170 and 1,712 patients, respectively; corresponding 6-month ABA retention rates were 80.2% and 77.1%. The NEG had fewer adverse drug reactions (14.5% vs. 17.2%, p =.021) and infections (4.8% vs. 7.2%, p =.002) than the EG. DAS28-CRP changed similarly between groups. The proportion of patients with low-risk/high-benefit and high-risk/low-benefit were 33.1% and 6.9% (NEG) and 29.7% and 9.0% (EG). Low-risk/high-benefit patients were younger, had shorter disease duration and fewer comorbidities, and were with less use of oral glucocorticoid and prior biologics, more use of methotrexate and higher DAS28-CRP than high-risk/low-benefit patients at baseline. Conclusion: ABA was well tolerated and similarly efficacious in the EG and NEG. Identification of factors related to low-risk/high-benefit may aid appropriate patient selection.

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