研究者詳細 - 竹内　勤

論文 - 竹内　勤

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Bendamustine increases interleukin-10 secretion from B cells via p38 MAP kinase activation

Lu L., Yoshimoto K., Morita A., Kameda H., Takeuchi T.

International Immunopharmacology （International Immunopharmacology） 39 273 - 279 2016年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1567-5769

© 2016 Elsevier B.V. We investigated the effects of bendamustine on B cell functions and explored potential clinical applications of the drugs to autoimmune diseases. Proliferation of Ramos cells, a human B cell line, was significantly inhibited by 25–100 μM of bendamustine in a dose-dependent manner. Concordantly, IgM secretion from Ramos cells was significantly inhibited at these concentrations by up to 70%. Interestingly, however, the production and secretion of interleukin-10 (IL-10) were dramatically (at least > 10-fold) increased by bendamustine at growth inhibitory concentrations. Exploration of the molecular mechanism of IL-10 production revealed that bendamustine enhanced the phosphorylation of p38 MAP kinase. Further, Sp1 was identified as a downstream transcription factor, and the inhibition of p38 MAP kinase and Sp1 with their inhibitors led to the abrogation of bendamustine-induced IL-10 production and the DNA binding of Sp1. Importantly, when PBMC from healthy donors were cultured with bendamustine at the concentration of 30 μM, under the stimulation with an anti-IgM antibody, an anti-CD40 antibody, recombinant human IL-21 (rhIL-21) and recombinant human soluble BAFF (rhsBAFF), IL-10 production by B cells (CD20+CD4-CD8-CD14-) among peripheral blood mononuclear cell (PBMC) was significantly enhanced by adding bendamustine. These results collectively suggest that the p38 MAP kinase-Sp1 pathway plays a crucial role in bendamustine-induced IL-10 production by B cells. Our findings suggest a novel therapeutic possibility for autoimmune diseases through the upregulation of IL-10 which has an anti-inflammatory effects.

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Safety and efficacy of CT-P13 in Japanese patients with rheumatoid arthritis in an extension phase or after switching from infliximab

竹内勤

Modern Rheumatology （Modern Rheumatology） 27 （ 2 ） 237 - 245 2016年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 14397595

© 2016 Japan College of Rheumatology. Published by Informa UK Limited, trading as Taylor & Francis Group. Objectives: This study aimed to evaluate the safety of CT-P13 in patients with rheumatoid arthritis (RA) during long-term treatment or after switching from innovator infliximab (IFX). Methods: Patients who completed 54 weeks of treatment in a phase I/II study (PI/II) received CT-P13 at an initial dose of 3 mg/kg at Week 62, with dose increases permitted up to 10 mg/kg. The primary endpoint was adverse event (AE) incidence. Results: Thirty-four of 38 patients in the maintenance group and 29 of 33 in the switch group reported at least one AE. Safety profiles in both groups were similar to those in PI/II. Eleven of 28 patients who were positive for anti-drug antibodies (ADA) at Week 62 discontinued the study before Week 110. Forty-one of 43 ADA-negative patients remained negative, and 10 of 28 ADA-positive patients became negative during the study. The mean DAS28 (ESR) at Week 134 was 3.166 in the maintenance group and 3.955 in the switch group. Conclusions: CT-P13 was well tolerated in patients who maintained the treatment after 54 weeks and in patients who switched to CT-P13 after 54 weeks of IFX treatment. The study also demonstrated a stable clinical efficacy of CT-P13 in RA patients.

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Toreforant, a histamine H4 receptor antagonist, in patients with active rheumatoid arthritis despite methotrexate therapy: Results of 2 phase II studies

Thurmond R., Greenspan A., Radziszewski W., Xu X., Miao Y., Chen B., Ge T., Zhou B., Baker D., Pavlova D., Ritchlin C., Tanaka Y., Takeuchi T., Smolen J.

Journal of Rheumatology （Journal of Rheumatology） 43 （ 9 ） 1637 - 1642 2016年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

Copyright © 2016. All rights reserved. Objective. To assess toreforant (selective histamine H 4 receptor antagonist) in active rheumatoid arthritis (RA). Methods. In a phase IIa, double-blind, placebo-controlled test, 86 patients were randomized (2:1) to once-daily toreforant 100 mg or placebo for 12 weeks. In phase IIb, double-blind, placebo-controlled, dose-range-finding evaluations, 272 patients were randomized (1:1:1:1) to once-daily placebo or toreforant 3/10/30 mg. Primary efficacy endpoints for both studies were Week 12 changes in 28-joint Disease Activity Score-C-reactive protein (DAS28-CRP). Results. Phase IIa testing was terminated prematurely (patient fatality; secondary hemophagocytic lymphohistiocytosis). Posthoc analyses indicated toreforant 100 mg/day reduced RA signs/symptoms through Week 12. Phase IIb testing, however, showed no significant Week 12 improvement in DAS28-CRP with toreforant. Conclusion. Toreforant was not effective in phase IIb testing.

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Discontinuation of etanercept after achievement of sustained remission in patients with rheumatoid arthritis who initially had moderate disease activity—results from the ENCOURAGE study, a prospective, international, multicenter randomized study

Yamanaka H., Nagaoka S., Lee S., Bae S., Kasama T., Kobayashi H., Nishioka Y., Ueki Y., Seto Y., Nishinarita M., Tamura N., Kimura N., Saito K., Tomita T., Nawata Y., Suzuki S., Ishigatsubo Y., Munakata Y., Makino Y., Inoue E., Tanaka Y., Takeuchi T.

Modern Rheumatology （Modern Rheumatology） 26 （ 5 ） 651 - 661 2016年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2015 Japan College of Rheumatology. Objectives: To investigate the efficacy and safety of etanercept (ETN) in patients with rheumatoid arthritis (RA) with moderate disease activity and the possibility to discontinue ETN after achieving remission. Methods: Multicenter, randomized, and open-label study was conducted in Japan and Korea. RA patients (disease duration <5 years) with moderate disease activity despite methotrexate (MTX) treatment were allocated to either MTX or ETN + MTX (Period 1) for 12 months. Patients who achieved sustained remission defined as DAS28 < 2.6 at both 6 and 12 months in the ETN + MTX group, were randomized to either continue or discontinue ETN for 12 months (Period 2). Results: A total of 222 patients were enrolled in Period 1 and clinical remission was achieved in 106/157 (67.5%) and 5/28 (17.9%) patients in the ETN + MTX and MTX groups, respectively. In Period 2, sixty-seven patients were randomized and finally 28/32 (87.5%) and 15/28 (53.6%) patients who continued or discontinued ETN maintained clinical remission. Baseline disease activity and the presence of comorbid diseases influenced the maintenance of remission after ETN discontinuation. Conclusions: ETN + MTX was efficient for RA patients with moderate disease activity into remission. After achieving sustained remission, a half of the patients who discontinued ETN could maintain remission for 1 year.

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Polychondritis presenting with oculomotor and abducens nerve palsies as the initial manifestation

Akiyama M., Kaneko Y., Hanaoka H., Kuwana M., Takeuchi T.

Modern Rheumatology （Modern Rheumatology） 26 （ 5 ） 790 - 793 2016年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2014 Japan College of Rheumatology. We treated a patient with relapsing polychondritis (RP) who presented with intermittent oculomotor and abducens nerve palsies as the first manifestation. Ear swelling and laryngeal edema emerged 7 months later, which led us to diagnose him with RP. Moderate doses of glucocorticoid resolved all symptoms. Our experience with RP accompanied by oculomotor nerve palsy suggests that RP should be considered in patients with cranial nerve palsies so that they may be promptly diagnosed and treated.

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Efficacy and safety of tabalumab plus standard of care in Japanese patients with active systemic lupus erythematosus: Subgroup analyses of the ILLUMINATE-1 study

Tanaka Y., Takeuchi T., Akashi N., Takita Y., Kovacs B., Kariyasu S.

Modern Rheumatology （Modern Rheumatology） 27 （ 2 ） 284 - 291 2016年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2016 Japan College of Rheumatology. Objective: To assess the efficacy and safety of tabalumab, an anti-B cell activating factor (BAFF) antibody, in combination with standard of care (SoC) therapy in Japanese patients with active systemic lupus erythematosus (SLE). Methods: A subgroup analysis was conducted in Japanese patients (n = 45) enrolled in ILLUMINATE-1, a phase III global trial in SLE patients (N = 1164). Patients received SoC plus tabalumab or placebo, starting with a loading dose (240 mg) at week 0, followed by 120 mg every 4 weeks (120 Q4W, n = 15), 120 mg every 2 weeks (120 Q2W, n = 15), or placebo Q2W (n = 15). The primary endpoint was proportion achieving SLE Responder Index-5 (SRI-5) improvement at week 52. Results: A numerically greater SRI-5 response rate was achieved with 120 Q2W (46.7%; p = 0.059 vs. placebo) compared with 120 Q4W (20.0%) and placebo Q2W (13.3%). The proportion of patients with severe SLE flare was lower for 120 Q2W (0%) and 120 Q4W (6.7%) than for placebo (26.7%). The rates of serious adverse events (AEs) and treatment-emergent AEs were similar across treatments. Conclusion: In Japanese SLE patients, tabalumab 120 Q2W improved SRI-5 response rate and reduced the frequency of severe flares compared with placebo. Safety profiles were similar with tabalumab and placebo.

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Identification of baseline gene expression signatures predicting therapeutic responses to three biologic agents in rheumatoid arthritis: A retrospective observational study

Nakamura S., Suzuki K., Iijima H., Hata Y., Lim C., Ishizawa Y., Kameda H., Amano K., Matsubara K., Matoba R., Takeuchi T.

Arthritis Research and Therapy （Arthritis Research and Therapy） 18 （ 1 ） 159 2016年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1478-6354

© 2016 The Author(s). Background: According to EULAR recommendations, biologic DMARDs (bDMARDs) such as tumor necrosis factor inhibitor, tocilizumab (TCZ), and abatacept (ABT) are in parallel when prescribing to rheumatoid arthritis (RA) patients who have shown insufficient response to conventional synthetic DMARDs. However, most prediction studies of therapeutic response to bDMARDs using gene expression profiles were focused on a single bDMARD, and consideration of the results from the perspective of RA pathophysiology was insufficient. The aim of this study was to identify the specific molecular biological features predicting the therapeutic outcomes of three bDMARDs (infliximab [IFX], TCZ, and ABT) by studying blood gene expression signatures of patients before biologic treatment in a unified test platform. Methods: RA patients who responded inadequately to methotrexate and were later commenced on any one of IFX (n = 140), TCZ (n = 38), or ABT (n = 31) as their first biologic between May 2007 and November 2011 were enrolled. Whole-blood gene expression data were obtained before biologic administration. Patients were categorized into remission (REM) and nonremission (NON-REM) groups according to CDAI at 6 months of biologic therapy. We employed Gene Set Enrichment Analysis (GSEA) to identify functional gene sets differentially expressed between these two groups for each biologic. Then, we compiled "signature scores" for these gene sets, and the prediction performances were assessed. Results: GSEA showed that inflammasome genes were significantly upregulated with IFX in the NON-REM group compared with the REM group. With TCZ in the REM group, B-cell-specifically expressed genes were upregulated. RNA elongation, apoptosis-related, and NK-cell-specifically expressed genes were upregulated with ABT in the NON-REM group. Logistic regression analyses showed that "signature scores" of inflammasomes, B-cell-specifically expressed, and NK-cell-specifically expressed genes were significant, independently predictive factors for treatment outcome with IFX, TCZ, and ABT, respectively. The AUCs of ROC curves of these signature scores were 0.637, 0.796, and 0.768 for IFX, TCZ, and ABT, respectively. Conclusions: We have identified original gene expression predictive signatures uniquely underlying the therapeutic effects of IFX, TCZ, and ABT. This is, to our knowledge, the first attempt to predict therapeutic effects of three drugs concomitantly using a unified gene expression test platform.

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Enhanced IgG4 production by follicular helper 2 T cells and the involvement of follicular helper 1 T cells in the pathogenesis of IgG4-related disease

Akiyama M., Yasuoka H., Yamaoka K., Suzuki K., Kaneko Y., Kondo H., Kassai Y., Koga K., Miyazaki T., Morita R., Yoshimura A., Takeuchi T.

Arthritis Research and Therapy （Arthritis Research and Therapy） 18 （ 1 ） 167 2016年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1478-6354

© 2016 The Author(s). Background: The aim of this study was to elucidate the function of circulating follicular helper T (Tfh) cell subsets in helping B cells in patients with active, untreated IgG4-related disease (IgG4-RD) and determine their relationship with disease activity. Methods: Seventeen consecutive patients with active, untreated IgG4-RD, 20 with primary Sjögren syndrome (pSS), 5 with multicentric Castleman's disease (MCD), and 12 healthy controls (HC) were enrolled. Tfh cell subset function was evaluated by co-culture with naïve B cells in vitro. Activated Tfh cell subsets were defined as a CCR7lowPD-1high subset among Tfh cell subsets. Disease activity was evaluated by IgG4-RD responder index (IgG4-RD RI) score. Results: The number of Tfh2 cells was significantly higher in IgG4-RD compared to pSS, MCD, or HC, and correlated with serum IgG4 level or the number of plasmablasts. In vitro, Tfh2 cells more efficiently induced the differentiation of naïve B cells into plasmablasts compared to Tfh1 or Tfh17 cells. Of note, while IgG production in culture supernatants of Tfh2 cells was comparable between IgG4-RD and HC, IgG4 production was significantly higher with Tfh2 cells from patients with IgG4-RD than in those from HC. Accordingly, the IgG4:IgG ratio in culture supernatants was also significantly higher with Tfh2 cells from IgG4-RD compared to HC. Moreover, the number of activated Tfh2 cells was higher in IgG4-RD compared to pSS, MCD, or HC, and strongly correlated with IgG4-RD RI score in the baseline active phase. Particularly, the number of activated Tfh2 cells was associated with the number of affected organs and serum IgG4 level. Importantly, the number of activated Tfh2 cells was decreased after glucocorticoid treatment and paralleled disease improvement. Moreover, the number of activated Tfh1 cells was also increased in IgG4-RD compared to pSS, MCD, or HC, correlating with IgG4-RD RI score, but not with serum IgG4 level. Conclusions: Tfh2 cells, but not Tfh1 or Tfh17 cells, induce the differentiation of naïve B cells into plasmablasts and enhanced production of IgG4 in patients with active, untreated IgG4-RD. Furthermore, activated Tfh2 cells reflect disease activity, suggesting the involvement of this T cell subset in the pathogenesis of IgG4-RD. Interestingly, the number of activated Tfh1 cells was also increased in IgG4-RD, correlating with disease activity but not with serum IgG4 level, suggesting the involvement of Tfh1 cells but not in the process of IgG4 production in patients with IgG4-RD.

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Efficacy of denosumab combined with bDMARDs on radiographic progression in rheumatoid arthritis

Hasegawa Tetsuo, Kaneko Yuko, Izumi Keisuke, Takeuchi Tsutomu

Joint Bone Spine 84 （ 3 ） 379 - 380 2016年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1297-319X

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Effect of denosumab on Japanese patients with rheumatoid arthritis: A dose-response study of AMG 162 (Denosumab) in patients with rheumatoid arthritis on methotrexate to validate inhibitory effect on bone erosion (DRIVE) - A 12-month, multicentre, randomised, double-blind, placebo-controlled, phase II clinical trial

Takeuchi T., Tanaka Y., Ishiguro N., Yamanaka H., Yoneda T., Ohira T., Okubo N., Genant H., Van Der Heijde D.

Annals of the Rheumatic Diseases （Annals of the Rheumatic Diseases） 75 （ 6 ） 983 - 990 2016年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

Objectives To evaluate efficacy and safety of three different regimens of denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor kappa B (RANK) ligand (RANKL), for Japanese patients with rheumatoid arthritis (RA). Methods In this multicentre, randomised, placebocontrolled phase II study, 350 Japanese patients with RA between 6 months and <5 years, stratified by glucocorticoid use and rheumatoid factor status, were randomly assigned to subcutaneous injections of placebo or denosumab 60 mg every 6 months (Q6M), every 3 months (Q3M) or every 2 months (Q2M). All patients basically continued methotrexate treatment and had a supplement of calcium and vitamin D throughout the study. The primary endpoint was change in the modified Sharp erosion score from baseline to 12 months. Results Denosumab significantly inhibited the progression of bone erosion at 12 months compared with the placebo, and the mean changes of the modified Sharp erosion score at 12 months from baseline were 0.99, 0.27 (compared with placebo, p=0.0082), 0.14 (p=0.0036) and 0.09 (p<0.0001) in the placebo, Q6M, Q3M and Q2M, respectively. Secondary endpoint analysis revealed that denosumab also significantly inhibited the increase of the modified total Sharp score compared with the placebo, with no obvious evidence of an effect on joint space narrowing for denosumab. As shown in previous studies, denosumab increased bone mineral density. No apparent difference was observed in the safety profiles of denosumab and placebo. Conclusions Addition of denosumab to methotrexate has potential as a new therapeutic option for patients with RA with risk factors of joint destruction.

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Post-hoc analysis showing better clinical response with the loading dose of certolizumab pegol in Japanese patients with active rheumatoid arthritis

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

Modern Rheumatology （Modern Rheumatology） 26 （ 4 ） 473 - 480 2016年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2015 Japan College of Rheumatology. Objectives: To compare the efficacy and safety of certolizumab pegol (CZP) with and without loading dose (LD) in a post-hoc analysis of two Japanese clinical studies. Methods: Data from the double-blind trials (DBT) J-RAPID and HIKARI, and their open-label extension (OLE) studies, were used. Patients randomized to CZP 200 mg every 2 weeks (Q2W) groups starting with LD (400 mg Weeks 0/2/4; LD group; J-RAPID: n = 82, HIKARI: n = 116) and patients randomized to placebo groups who subsequently started CZP Q2W without LD in the OLEs (No-LD group; J-RAPID: n = 61, HIKARI: n = 99) were analyzed. Efficacy and pharmacokinetics were assessed during 24 weeks. Adverse events were reported from all studies. Results: In both trials, the LD groups showed more rapid initial ACR20/50/70 kinetics, and maintained higher ACR50/70 responses until 24 weeks, compared with the No-LD groups. Anti-CZP antibody development was less frequent in the LD groups (J-RAPID: 1.2% versus 4.9%; HIKARI: 17.2% versus 27.3%). Similar safety profiles were reported between LD and No-LD groups (any AEs: 281.8 versus 315.7 [J-RAPID], 282.6 versus 321.3 [HIKARI] [incidence rate/100 patient-years]). Conclusions: Despite limitations, including comparing DBT and OLE studies, these results suggest that a CZP LD improves clinical response in active rheumatoid arthritis without altering the safety profile.

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Clinical efficacy, radiographic progression, and safety through 156 weeks of therapy with subcutaneous golimumab in combination with methotrexate in Japanese patients with active rheumatoid arthritis despite prior methotrexate therapy: final results of the randomized GO-FORTH trial

Tanaka Y., Harigai M., Takeuchi T., Yamanaka H., Ishiguro N., Yamamoto K., Miyasaka N., Koike T., Baker D., Ishii Y., Yoshinari T.

Modern Rheumatology （Modern Rheumatology） 26 （ 4 ） 481 - 490 2016年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2015 Japan College of Rheumatology. Objective: To evaluate the safety and efficacy of golimumab + methotrexate (MTX) in Japanese patients with active rheumatoid arthritis (RA). Methods: Japanese patients with active RA despite MTX were randomized to placebo + MTX (Group 1, n = 88), golimumab 50 mg + MTX (Group 2, n = 86), or golimumab 100 mg + MTX (Group 3, n = 87). Patients with <20% improvement in swollen/tender joint counts entered early escape at week 16. At week 24, all remaining placebo patients crossed over to golimumab 50 mg. Efficacy assessments included ACR20, DAS28-ESR, and HAQ-DI. Radiographic progression was assessed with the van der Heijde-modified Sharp (vdH-S) score. Results: ACR20 response rates in Group 1, Group 2, and Group 3 were 67.9, 86.1, and 82.4%, respectively, at week 52 and were maintained through week 104 (87.1, 94.0, and 88.7%) and week 156 (97.1, 94.1, and 89.5%). Proportions of patients with good/moderate DAS28-ESR response or clinically meaningful improvement in HAQ-DI were also maintained through week 156. The majority of patients did not experience radiographic progression through week 156. Among 257 golimumab-treated patients, 251 (97.7%) had ≥1 AE; 54 (21.0%) had ≥1 serious AE through week 156. Infections were the most common type of AE. Conclusions: Response to golimumab + MTX was maintained over 3 years in Japanese patients with active RA despite MTX. Safety results were consistent with the known safety profile of golimumab.

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Akiyama M., Kaneko Y., Hayashi Y., Takeuchi T.

Medicine (United States) （Medicine (United States)） 95 （ 24 ） e3970 2016年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0025-7974

© 2016 Wolters Kluwer Health, Inc. All rights reserved. Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized new disease entity characterized by elevated serum IgG4 and infiltration of IgG4+ plasma cells in affected tissues. Histological examination is essential for definitive diagnosis, as other pathological conditions can also present with serum IgG4 elevation. However, IgG4-RD frequently involves vital or internal organs that are difficult to perform biopsies. We herein report a unique case of IgG4-RD involving vital organs that could be successfully diagnosed by alternative lip biopsy, an accessible, little invasive procedure, despite no apparent manifestation demonstrating the involvement in labial salivary gland. A 60-year-old man with swelling of both submandibular glands and elevated serum creatinine level visited our hospital. His labial salivary glands appeared normal. His blood test showed high serum IgG4, and positron-emission computed tomography revealed abnormal uptake in submandibular glands, periaorta, and left kidney with hydronephrosis. We suspected him of IgG4-RD; however, the involved organs were difficult to approach for histological examination. Alternatively, we performed lip biopsy and proved massive infiltration of IgG4+ plasma cells leading to the diagnosis with IgG4-RD. Treatment with prednisolone resulted in the remarkable improvement of organ involvements and the normalization of serum IgG4 level after 3 months. Prednisolone was gradually tapered without the relapse of disease. The early recognition and diagnosis of IgG4-RD is clinically important because delay in the treatment initiation leads to fibrosis with irreversible organ damage. Our case highlights the possibility that lip biopsy is a promising option for histological examination in patients with IgG4-RD in whom affected organs are difficult to access, leading to early diagnosis with appropriate treatment.

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Methotrexate-associated intravascular large B-cell lymphoma in a patient with rheumatoid arthritis

Kikuchi J., Kaneko Y., Kasahara H., Emoto K., Kubo A., Okamoto S., Takeuchi T.

Internal Medicine （Internal Medicine） 55 （ 12 ） 1661 - 1665 2016年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0918-2918

© 2016 The Japanese Society of Internal Medicine. Intravascular large B-cell lymphoma (IVLBCL) is a rare and clinically aggressive lymphoma with an unfavorable prognosis. We report the case of a 50-year-old woman who was diagnosed with IVLBCL during treatment with methotrexate (MTX) and biologic agents for rheumatoid arthritis. The symptoms showed partial improvement only after the cessation of both treatments. She subsequently received chemotherapy and achieved a complete remission and has remained free of recurrence for 2 years without any further treatment. We herein describe a rare case of IVLBCL which presented with the features of an MTX-associated lymphoproliferative disorder.

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Efficacy and safety of the oral Janus kinase inhibitor peficitinib (ASP015K) monotherapy in patients with moderate to severe rheumatoid arthritis in Japan: A 12-week, randomised, double-blind, placebo-controlled phase IIb study

Takeuchi T., Tanaka Y., Iwasaki M., Ishikura H., Saeki S., Kaneko Y.

Annals of the Rheumatic Diseases （Annals of the Rheumatic Diseases） 75 （ 6 ） 1057 - 1064 2016年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

Objective To evaluate the efficacy, safety and dose response of a novel oral Janus kinase inhibitor, peficitinib (ASP015K), as monotherapy in Japanese patients with moderate to severe rheumatoid arthritis (RA). Methods In a 12-week, double-blind study, 281 adult patients with RA with active disease not on concomitant disease-modifying antirheumatic drug therapy were randomised equally to once-daily placebo or peficitinib 25, 50, 100 and 150 mg. The primary endpoint was American College of Rheumatology (ACR) 20 response in the peficitinib treatment groups versus placebo at week 12. Results Mean age was 53.0 years, 81.1% were female and 25.3% had previously used antitumour necrosis factor therapy. Peficitinib 50, 100 and 150 mg each showed statistically significantly higher ACR20 response rates compared with placebo, and response rates increased up to 150 mg with a statistically significant dose response. The total incidence of treatmentemergent adverse events (TEAEs) was similar between the placebo (64.3%) and peficitinib 25, 50, 100 and 150 mg groups (70.9%, 64.9%, 52.7% and 67.2%, respectively). TEAEs occurring more frequently in the peficitinib group compared with the placebo group included nasopharyngitis, increased blood creatine phosphokinase and diarrhoea. No cases of serious infections were reported. Herpes zoster occurred in four patients (two each in peficitinib 25 and 100 mg). Conclusions Treatment with peficitinib as monotherapy for 12 weeks in Japanese patients with moderate to severe RA is efficacious and showed acceptable safety profile. These findings support further developments of peficitinib for RA treatment.

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IL-6 blockade

Kaneko Y., Takeuchi T.

Nihon rinsho. Japanese journal of clinical medicine （Nihon rinsho. Japanese journal of clinical medicine） 74 （ 6 ） 963 - 967 2016年06月

研究論文（学術雑誌）, 査読有り, ISSN 00471852

Interleukin-6 (IL-6) plays an important role in the pathogenesis of rheumatoid arthritis (RA). Tocilizumab, anti-human IL-6 receptor monoclonal antibody developed in Japan, prevents IL-6 from binding to IL-6 receptor blocking IL-6 signal. The clinical and radiographic efficacy of tocilizumab has proved in many clinical studies. Tocilizumab monotherapy is superior to methotrexate, which has not proved in TNF inhibitors, although tocilizuab in combination with methotrexate is more effective than tocilizumab monotherapy in inducing remission. Hepatotoxicity and infection are adverse events to be careful about.

Alteration of matrix metalloproteinase-3 O-glycan structure as a biomarker for disease activity of rheumatoid arthritis

Takeshita M., Kuno A., Suzuki K., Matsuda A., Shimazaki H., Nakagawa T., Otomo Y., Kabe Y., Suematsu M., Narimatsu H., Takeuchi T.

Arthritis Research and Therapy （Arthritis Research and Therapy） 18 （ 1 ） 112 2016年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1478-6354

© 2016 Takeshita et al. Background: Nearly all secreted proteins are glycosylated, and serum glycoproteins that exhibit disease-associated glycosylation changes have potential to be biomarkers. In rheumatoid arthritis (RA), C-reactive protein (CRP), and matrix metalloproteinase-3 (MMP-3) are widely used as serologic biomarkers, but they lack sufficient specificity or precision. We performed comparative glycosylation profiling of MMP-3 using a recently developed antibody-overlay lectin microarray technology that allows semicomprehensive and quantitative analysis of specific protein glycosylation to develop an RA-specific disease activity biomarker. Methods: Serum was taken from patients with RA (n = 24) whose disease activity was scored using composite measures, and MMP-3 was immunoprecipitated and subjected to lectin microarray analysis. A disease activity index (DAI) based on lectin signal was developed and validated using another cohort (n = 60). Synovial fluid MMP-3 in patients with RA and patients with osteoarthritis (OA) was also analyzed. Results: Intense signals were observed on a sialic acid-binding lectin (Agrocybe cylindracea galectin [ACG]) and O-glycan-binding lectins (Jacalin, Agaricus bisporus agglutinin [ABA], and Amaranthus caudatus agglutinin [ACA]) by applying subnanogram levels of serum MMP-3. ACG, ABA, and ACA revealed differences in MMP-3 quantity, and Jacalin revealed differences in MMP-3 quality. The resultant index, ACG/Jacalin, correlated well with disease activity. Further validation using another cohort confirmed that this index correlated well with several DAIs and their components, and reflected DAI changes following RA treatment, with correlations greater than those for MMP-3 and CRP. Furthermore, MMP-3, which generated a high ACG/Jacalin score, accumulated in synovial fluid of patients with RA but not in that of patients with OA. Sialidase digestion revealed that the difference in quality was derived from O-glycan α-2,6-sialylation. Conclusions: This is the first report of a glycoprotein biomarker using glycan change at a local lesion to assess disease activity in autoimmune diseases. Differences in the degree of serum MMP-3 α-2,6-sialylation may be a useful index for estimating disease activity.

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Identification of definitive serum biomarkers associated with disease activity in primary Sjögren's syndrome

Nishikawa A., Suzuki K., Kassai Y., Gotou Y., Takiguchi M., Miyazaki T., Yoshimoto K., Yasuoka H., Yamaoka K., Morita R., Yoshimura A., Takeuchi T.

Arthritis Research and Therapy （Arthritis Research and Therapy） 18 （ 1 ） 106 2016年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1478-6354

© 2016 Nishikawa et al. Background: In this study, we sought to identify definitive biomarkers associated with disease activity in primary Sjögren's syndrome (pSS). Methods: Serum protein concentrations in pSS patients and healthy controls (HCs) were comprehensively screened using high-throughput proteomic analysis, and differentially expressed proteins were extracted. Correlation between differentially expressed proteins and European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI) scores was analyzed and disease activity-associated biomarkers were identified. These biomarkers were validated by enzyme-linked immunosorbent assay (ELISA) in a separate pSS cohort. Results: The serum concentrations of 1100 proteins were compared between 30 pSS patients and 30 HCs, with 82 differentially expressed proteins identified as pSS-associated proteins. Of these 82 proteins, 9 were identified as disease activity-associated biomarkers. These nine biomarkers underwent validation by ELISA in a separate pSS validation cohort (n = 58), with five proteins (CXCL13, TNF-R2, CD48, B-cell activating factor (BAFF), and PD-L2) subsequently being confirmed as candidate biomarkers. Of these five candidate biomarkers, CXCL13 exhibited the most significant correlation with the lymphadenopathy, glandular, and pulmonary domains of the ESSDAI. CXCL13, TNF-R2 and CD48 exhibited a positive correlation with the biological domain of the ESSDAI. TNF-R2 exhibited the most negative correlation with uptake in the submandibular gland on technetium 99m-pertechnetate salivary gland scintigraphy. Conclusions: Our approach successfully identified serum biomarkers associated with disease activity in pSS patients. These markers might be potential therapeutic targets in pSS patients.

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Enlargement of thymoma triggers overlapping autoimmune diseases

Shiihashi Gen, Kaneko Yuko, Suzuki Shigeaki, Hanaoka Hironari, Nakahara Jin, Takeuchi Tsutomu, Suzuki Norihiro

Autoimmunity Reviews 15 （ 12 ） 1200 - 1201 2016年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1568-9972

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Association of disease activity with acute exacerbation of interstitial lung disease during tocilizumab treatment in patients with rheumatoid arthritis: a retrospective, case–control study

Akiyama M., Kaneko Y., Yamaoka K., Kondo H., Takeuchi T.

Rheumatology International （Rheumatology International） 36 （ 6 ） 881 - 889 2016年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0172-8172

© 2016, Springer-Verlag Berlin Heidelberg. The objective of the study was to identify risk factors for acute exacerbation of interstitial lung disease (ILD) during tocilizumab treatment in patients with rheumatoid arthritis (RA). This is a retrospective, case–control study. We reviewed 395 consecutive RA patients who received tocilizumab. First, we divided the patients according to the presence (RA-ILD) or absence of ILD (non-ILD) assessed by chest X-ray or high-resolution computed tomography, and compared them for characteristics relevant to RA-ILD. Subsequently, focusing on the patients with RA-ILD, we assessed their baseline characteristics and clinical courses comparing patients with acute exacerbation to those without. Comparing 78 with ILD and 317 without ILD, the following were identified as factors related to RA-ILD on multivariate analysis: age 60 years or older (OR 4.5, 95 % CI 2.2–9.4, P < 0.0001), smoking habit (OR 2.9, 95 % CI 1.5–5.5, P = 0.002), and high rheumatoid factor levels (OR 2.8, 95 % CI 1.4–5.5, P = 0.002). Of 78 RA-ILD patients, six developed acute exacerbation during tocilizumab treatment. The median duration between the initiation of tocilizumab treatment and the acute exacerbation occurrence was 48 weeks. While baseline characteristics did not differ between acute exacerbation and non-acute exacerbation groups, patients experiencing acute exacerbation had significantly higher Clinical Disease Activity Index (CDAI) at 24 weeks (20.8 vs. 6.2, P = 0.019). Univariate analysis showed that CDAI > 10 at 24 weeks was a risk factor for acute exacerbation (OR 4.7, 95 % CI 2.1–10.4, P = 0.02). Uncontrolled arthritis activity during tocilizumab treatment may be associated with acute exacerbation of RA-ILD, suggesting post-treatment monitoring of disease activity is important not only with respect to RA itself but also for RA-ILD.

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