研究者詳細 - 竹内　勤

論文 - 竹内　勤

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The efficacy and safety of subcutaneous clazakizumab in patients with moderate-to-severe rheumatoid arthritis and an inadequate response to methotrexate: results from a multinational, phase IIb, randomized, double-blind, placebo/active-controlled, dose-ranging study

Weinblatt M., Mease P., Mysler E., Takeuchi T., Drescher E., Berman A., Xing J., Zilberstein M., Banerjee S., Emery P.

Arthritis & rheumatology (Hoboken, N.J.) （Arthritis & rheumatology (Hoboken, N.J.)） 67 （ 10 ） 2591 - 2600 2015年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2326-5191

© 2015, American College of Rheumatology. OBJECTIVE: Clazakizumab is a humanized monoclonal antibody that binds to the interleukin-6 (IL-6) cytokine. This study was undertaken to evaluate the efficacy and safety of clazakizumab in combination with methotrexate (MTX) or clazakizumab monotherapy versus MTX alone in patients with rheumatoid arthritis (RA) and an inadequate response to MTX.METHODS: In this multinational, phase IIb, randomized, double-blind, placebo-controlled, dose-ranging study, patients were randomized to receive 1) once-monthly subcutaneous (SC) clazakizumab at 25, 100, or 200 mg plus MTX, 2) once-monthly SC clazakizumab at 100 mg or 200 mg as monotherapy, or 3) MTX plus placebo (i.e., MTX alone). Adalimumab (40 mg) plus MTX was included as an active reference. The primary end point was the American College of Rheumatology 20% (ACR20) improvement response rate at week 12. Secondary end points included ACR20, ACR50, and ACR70 response rates as well as protocol-defined remission rates and Health Assessment Questionnaire disability index scores at weeks 12 and 24.RESULTS: In total, 418 patients were randomized, and baseline characteristics were balanced across the treatment groups. Patients receving clazakizumab had significantly greater ACR20 response rates at week 12 compared with patients receiving MTX alone (76.3%, 73.3%, and 60.0% of patients in the clazakizumab 25, 100, and 200 mg plus MTX groups, respectively, and 55.0% and 61.0% of patients in the clazakizumab 100 and 200 mg monotherapy groups, respectively, versus 39.3% of patients receiving MTX alone; P < 0.05 for all comparisons). At week 24, all clazakizumab groups had higher ACR20, ACR50, and ACR70 response rates and higher remission rates compared with MTX alone. Rates of serious adverse events ranged from 8.3% to 13.6% in the clazakizumab treatment groups, compared with 3.3% in the MTX alone group. Changes in laboratory data were consistent with the pharmacologic effects of IL-6 blockade.CONCLUSION: In patients with RA and an inadequate response to MTX, treatment with clazakizumab in combination with MTX or clazakizumab monotherapy was well tolerated, and patients achieved significant improvements in disease activity, including higher rates of remission, as compared with patients receiving MTX alone.

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Infliximab and etanercept have distinct actions but similar effects on cytokine profiles in rheumatoid arthritis

Takeshita M., Suzuki K., Kikuchi J., Izumi K., Kurasawa T., Yoshimoto K., Amano K., Takeuchi T.

Cytokine （Cytokine） 75 （ 2 ） 222 - 227 2015年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1043-4666

© 2015 Elsevier Ltd. Objective: Pro-inflammatory cytokines, especially TNFα, play a central role in the pathogenesis of rheumatoid arthritis (RA). The available TNF inhibitors are only slightly different from one another in terms of clinical efficacy, at least at the group level, but their structures and modes of action are not identical. Infliximab (IFX) and etanercept (ETN) differ in their ability to induce antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, and in their ability to bind TNFβ. The purpose of our study was to elucidate the different cytokine pathways through which these two drugs enact their clinical efficacy. Methods: Serum from 44 RA patients treated with IFX and 24 patients treated with ETN was studied. All patients had been given these biologics at identical dosages and intervals for one year. The concentrations of 11 inflammatory cytokines and their receptors (IL-1β, IL-2, IL-6, IL-6R, IL-8, IL-10, IL-12, TNFα, TNFβ, IFNγ, and GM-CSF) were measured at weeks 0, 22, and 54 using a high-sensitivity electro-chemiluminescence assay. Cytokine profiles were analyzed along with clinical efficacy. Results: IL-6 was significantly decreased in the ETN. +. MTX and IFX. +. MTX groups, although not in the ETN-only group; this change was consistent with changes in disease activity. IFNγ was gradually increased only in the non-remission subgroup of the IFX group, and not at all in the ETN group. TNFβ increased after starting IFX regardless of clinical efficacy. Conclusion: IL-6 inhibition is a pathway affected by both IFX and ETN. In addition, IFNγ increase is a distinctive feature of the inefficacy of IFX.

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Sustainable Efficacy of Switching from Intravenous to Subcutaneous Tocilizumab Monotherapy in Patients with Rheumatoid Arthritis

Ogata A., Atsumi T., Fukuda T., Hirabayashi Y., Inaba M., Ishiguro N., Kai M., Kawabata D., Kida D., Kohsaka H., Matsumura R., Minota S., Mukai M., Sumida T., Takasugi K., Tamaki S., Takeuchi T., Ueda A., Yamamoto K., Yamanaka H., Yoshifuji H., Nomura A.

Arthritis Care and Research （Arthritis Care and Research） 67 （ 10 ） 1354 - 1362 2015年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2151-464X

© 2015 The Authors. Arthritis Care & Research is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology. Objective To evaluate the efficacy and safety of switching from intravenous (IV) tocilizumab (TCZ) to subcutaneous (SC) TCZ monotherapy in rheumatoid arthritis patients. Methods Patients who had completed 24 weeks of TCZ-SC (162 mg/2 weeks) or TCZ-IV (8 mg/kg/4 weeks) monotherapy in the double-blind period of the MUSASHI study were enrolled in an 84-week open-label extension period. All received TCZ-SC (162 mg/2 weeks) monotherapy. Effects of the IV to SC switch were evaluated at week 36 (12 weeks after switching). Results Overall, 319 patients received ≥1 dose of TCZ-SC during the open-label extension period; 160 switched from TCZ-IV to TCZ-SC (TCZ IV/SC) and 159 continued TCZ-SC (TCZ SC/SC). Disease Activity Score in 28 joints using the erythrocyte sedimentation rate clinical remission rates were 62.5% (100 of 160) for TCZ IV/SC and 50.0% (79 of 158) for TCZ SC/SC at week 24, and were maintained at 62.5% (100 of 160) and 57.0% (90 of 158), respectively, at week 36. In the TCZ IV/SC group, 9% of patients (9 of 100) who had achieved remission at week 24 could not maintain remission at week 36. In TCZ IV/SC patients weighing ≥70 kg, the percentage with a sufficient serum TCZ concentration (≥1 μg/ml) decreased from 90.9% (10 of 11) at week 24 to 45.5% (5 of 11) at week 36. Overall safety profiles were similar in TCZ IV/SC and TCZ SC/SC except for mild injection site reactions in TCZ IV/SC. Conclusion Efficacy is adequately maintained in most patients switching from TCZ-IV (8 mg/kg/4 weeks) to TCZ-SC (162 mg/2 weeks) monotherapy. Patients receiving TCZ-IV can switch to TCZ-SC without serious safety concerns. Clinical efficacy may be reduced after switching in some patients with high body weight.

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Evaluation of the pharmacokinetic equivalence and 54-week efficacy and safety of CT-P13 and innovator infliximab in Japanese patients with rheumatoid arthritis

Takeuchi T., Yamanaka H., Tanaka Y., Sakurai T., Saito K., Ohtsubo H., Lee S., Nambu Y.

Modern Rheumatology （Modern Rheumatology） 25 （ 6 ） 817 - 824 2015年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2015 The Author(s). Published by Japan College of Rheumatology. Objectives. To demonstrate the pharmacokinetic equivalence of CT-P13 and its innovator infliximab (IFX) in Japanese patients with rheumatoid arthritis (RA), and to compare the efficacy and safety of these drugs, administered for 54 weeks. Methods. In a randomized, double-blind, parallel-group, multicenter study, 3 mg/kg of CT-P13 or IFX, in combination with methotrexate (MTX) (6-16 mg/week), was administered for 54 weeks to Japanese active RA patients with an inadequate response to MTX, to demonstrate the pharmacokinetic equivalence, based on the area under the curve (AUCτ) (weeks 6-14) and Cmax (week 6) of these drugs, and to compare their efficacy and safety. Results. The CT-P13-to-IFX ratios (90% confidence intervals) of the geometric mean AUCτ and Cmax values in patients negative for antibodies to infliximab at week 14 were 111.62% (100.24-124.29%) and 104.09% (92.12-117.61%), respectively, demonstrating the pharmacokinetic equivalence of these drugs. In the full analysis set, CT-P13 and IFX showed comparable therapeutic effectiveness, as measured by the American College of Rheumatology, Disease Activity Score in 28 joints, the European League Against Rheumatism, and other efficacy criteria, at weeks 14 and 30. The incidence of adverse events was similar for these drugs. Conclusion. CT-P13 and IFX, administered at a dose of 3 mg/kg in combination with MTX to active RA patients, were pharmacokinetically equivalent and comparable in efficacy and safety.

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Long-term safety and efficacy of treatment with subcutaneous abatacept in Japanese patients with rheumatoid arthritis who are methotrexate inadequate responders

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

Modern Rheumatology （Modern Rheumatology） 25 （ 5 ） 665 - 671 2015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. Objective. To assess the long-term safety, immunogenicity, and efficacy of subcutaneous (SC) abatacept in combination with methotrexate (MTX) in Japanese patients with rheumatoid arthritis who were MTX inadequate responders, in a long-term extension (LTE) to a double-dummy, double-blind study (NCT01001832). Methods. Patients, who had previously received SC or intravenous (IV) abatacept with MTX (6-8 mg/week) for 24 weeks, received SC abatacept (125 mg/week) with MTX for an additional 52 weeks. Safety, immunogenicity, and efficacy were assessed. Results. The LTE included 112 patients. SC abatacept was generally well tolerated in the LTE, with no new safety signals. American College of Rheumatology 20, 50, and 70 response rates, disease activity score 28 (C-reactive protein) remission rates (< 2.6), and Health Assessment Questionnaire-Disability Index response rates (≥ 0.3 improvement from baseline) achieved at the end of the double-blind period were maintained over the LTE and were comparable in patients who received SC or IV abatacept in the double-blind period. Seropositivity for immunogenicity occurred in 4 (3.6%) patients. Self-injection of SC abatacept was well controlled and not associated with additional safety events. Conclusions. SC abatacept had acceptable safety and was well tolerated and effective over the LTE (76 weeks in total), with low rates of immunogenicity in Japanese patients.

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Early achievement of complete renal response predicts good long-term renal outcome and low systemic damage in newly diagnosed lupus nephritis class III or IV

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

Modern Rheumatology （Modern Rheumatology） 25 （ 5 ） 714 - 718 2015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. Objective. To identify predictors of long-term renal prognosis after induction therapy in patients with newly diagnosed lupus nephritis class III or IV. Methods. We retrospectively studied patients with newly diagnosed lupus nephritis class III or IV. We divided them into two groups according to the complete renal response (CR) status at 3 years after induction therapy. We compared baseline clinical characteristics, renal pathological findings, and time to achieve CR, and identified predictors. Patients were followed up for to 10 years to assess long-term systemic damage. Results. Eighteen patients with CR and 9 with non-CR were included. There were no significant differences in baseline characteristics. Early CR, which was defined as achieving CR at 3 months after induction therapy, was significantly associated with maintaining CR at 3 years (p = 0.012). Patients with early CR less frequently had flare in systemic manifestation compared with those without over 10 years (p = 0.026). Deterioration of systemic damage was observed more often in non-early CR patients than early CR patients at 10 years (p = 0.029). Conclusion. Achieving CR at 3 months after induction therapy may predict CR at 3 years, reduced organ damage, and a low incidence of disease flare for 10 years.

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Glomerulomegaly in lupus nephritis: A prognostic marker for renal outcomes

Hanaoka H., Kuwana M., Takeuchi T.

International Journal of Rheumatic Diseases （International Journal of Rheumatic Diseases） 18 （ 7 ） 768 - 775 2015年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1756-1841

© 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd. Aim: Glomerulomegaly refers to the abnormal enlargement of glomeruli and is associated with an increased risk of progressive chronic kidney disease (CKD). However, it has rarely been investigated in lupus nephritis (LN). We therefore assessed glomerulomegaly as a prognostic factor for renal pathology. Method: Patients with class III or IV LN were retrospectively recruited and divided into two groups according to complete renal response (CR) at 3 years after the initiation of induction therapy. Baseline clinical and renal pathological findings were compared to identify prognostic factors, and patients were followed for up to 10 years to assess long-term renal outcomes. Results: Nineteen patients with and 19 without CR on 3-year follow-up were analyzed. Long-term disease duration and high levels of proteinuria were frequently observed in patients without CR (P = 0.03 and P = 0.01, respectively) at baseline compared to those with CR. On renal pathological analysis, a significantly higher proportion of patients without CR had enlarged glomeruli than those with CR (P = 0.03) in analysis of segmentally or minimally affected glomeruli. On 10-year follow-up, a higher proportion of patients without enlarged glomeruli maintained CR compared to those with enlarged glomeruli (P = 0.004). Further, glomerular area and disease duration were significantly correlated (P = 0.04). Conclusions: Enlarged segmentally or minimally affected glomeruli at diagnosis of LN might predict a worse renal prognosis at 3 years after induction therapy. Mechanical glomerular injury might influence clinical outcomes. International Journal of Rheumatic Diseases

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Number of circulating follicular helper 2 T cells correlates with IgG4 and interleukin-4 levels and plasmablast numbers in IgG4-related disease

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

Arthritis and Rheumatology （Arthritis and Rheumatology） 67 （ 9 ） 2476 - 2481 2015年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2326-5191

© 2015, American College of Rheumatology. Objective To elucidate the pathologic role of follicular helper T (Tfh) cells and their subsets in active, untreated IgG4-related disease. Methods Fifteen patients with active, untreated, biopsy-proven IgG4-related disease, 24 patients with primary Sjögren's syndrome (SS), 12 patients with allergic rhinitis, and 23 healthy controls were evaluated. Tfh cells were defined as CD3+CD4+CXCR5+CD45RA- cells. Circulating Tfh cell subsets among CXCR5+CD45RA-CD4+ T cells were defined as Tfh17 cells (CXCR3-CCR6+), Tfh1 cells (CXCR3+CCR6-), or Tfh2 cells (CXCR3-CCR6-). CD19+CD20-CD27+CD38+ cells were defined as plasmablasts. Serum cytokine levels (interleukin-4 [IL-4], IL-10, IL-21, and IL-33) were measured by cytometric bead array or enzyme-linked immunosorbent assay. Results Patients with IgG4-related disease had significantly increased levels of Tfh2 cells compared to healthy controls or patients with primary SS or allergic rhinitis. Increased Tfh2 levels were strongly associated with increased serum IgG4 levels and the IgG4:IgG ratio in IgG4-related disease. A positive correlation was observed between Tfh2 counts, plasmablast counts, and serum IL-4 levels. Interestingly, levels of plasmablasts and serum IL-4 and IgG4 decreased after treatment with glucocorticoids, whereas no obvious change was observed in Tfh2 cell counts. Conclusion The Tfh2 cell count was specifically increased in IgG4-related disease and was correlated with elevated serum levels of IgG4 and IL-4 and plasmablast counts. Tfh2 cells were the only component that was not affected by glucocorticoid treatment, suggesting that Tfh2 cells are the cell type implicated in IgG4-related disease.

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Anti-signal recognition particle antibody in patients without inflammatory myopathy: A survey of 6180 patients with connective tissue diseases

Hanaoka H., Kaneko Y., Suzuki S., Takada T., Hirakata M., Takeuchi T., Kuwana M.

Scandinavian Journal of Rheumatology （Scandinavian Journal of Rheumatology） 45 （ 1 ） 1 - 5 2015年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0300-9742

© 2016 Informa Healthcare on license from Scandinavian Rheumatology Research Foundation. Objectives: To clarify the prevalence of anti-signal recognition particle (anti-SRP) antibody in connective tissue diseases (CTDs) and investigate the clinical characteristics of patients without inflammatory myopathy.Method: Sera from 6180 patients with CTD were examined by immunoprecipitation (IPP) assays, and the records of patients positive for anti-SRP antibody were reviewed retrospectively. The antibody against the 54-kDa protein of SRP (SRP54) was quantified by enzyme-linked immunosorbent assay (ELISA) in patients with anti-SRP antibody.Results: Of the 28 patients positive for anti-SRP antibody, nine (32.1%) did not have inflammatory myopathy. The clinical diagnoses and characteristics of those patients varied considerably. In patients with inflammatory myopathy, the index of anti-SRP54 was much higher than in those without myopathy (1.15 vs. 0.46; p = 0.036).Conclusions: The prevalence of anti-SRP antibody was 0.5% in a cohort of Japanese patients with CTD, and one-third of them did not have inflammatory myopathy. Sera from patients with inflammatory myopathy recognized SRP54 more strongly than in those without myopathy.

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Brief report: Leucine-rich α<inf>2</inf>-glycoprotein as a potential biomarker for joint inflammation during anti-interleukin-6 biologic therapy in rheumatoid arthritis

Fujimoto M., Serada S., Suzuki K., Nishikawa A., Ogata A., Nanki T., Hattori K., Kohsaka H., Miyasaka N., Takeuchi T., Naka T.

Arthritis and Rheumatology （Arthritis and Rheumatology） 67 （ 8 ） 2056 - 2060 2015年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2326-5191

© 2015, American College of Rheumatology. Objective To investigate whether leucine-rich α<inf>2</inf>-glycoprotein (LRG) could be a biomarker for disease activity during interleukin-6 (IL-6) blockade treatment of rheumatoid arthritis (RA). Methods In 59 RA patients who were treated with tocilizumab for 24 weeks, serum LRG levels were determined by enzyme-linked immunosorbent assay. RA disease activity was evaluated by the Clinical Disease Activity Index (CDAI). Receiver operating characteristic (ROC) curve analysis was used to examine the diagnostic performance of LRG and other biomarkers. In monkeys with experimental autoimmune arthritis, swollen joint counts, joint pathologic changes, and blood levels of C-reactive protein (CRP) and LRG were evaluated after treatment with anti-IL-6 receptor antibody. Results Among tocilizumab-treated RA patients, those with active disease (CDAI >2.8) had significantly higher serum LRG levels compared to those whose disease was in remission. ROC curve analysis suggested that the LRG level was more useful than the CRP or matrix metalloproteinase 3 level or the erythrocyte sedimentation rate in discriminating between remission and active disease during therapy with tocilizumab. In monkeys treated with IL-6 blockade, joint scores were more closely correlated with LRG levels than with CRP levels. Histologic analysis of joints revealed that LRG levels correlated significantly with granulomatous tissue formation, cartilage degeneration, and bone destruction in IL-6 blockade-treated monkeys with low levels of CRP. Conclusion Under conditions of IL-6 inhibition, LRG was more useful than other biomarkers in discriminating between active and inactive disease in human RA and in detecting joint inflammation in experimental arthritis. LRG may serve as a convenient biomarker for RA disease activity during IL-6 blockade treatment.

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Crohn’s disease in which the patient developed aortitis during treatment with adalimumab

Kiyohara H., Hisamatsu T., Matsuoka K., Naganuma M., Kameda H., Seta N., Takeuchi T., Kanai T.

Internal Medicine （Internal Medicine） 54 （ 14 ） 1725 - 1732 2015年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0918-2918

© 2015 The Japanese Society of Internal Medicine. A 23-year-old woman developed aortitis during treatment with adalimumab (ADA) for ileocolic Crohn’s disease (CD). The patient complained of a high fever, abdominal pain, diarrhea, hematochezia and arthralgia. Although the ADA therapy resulted in immediate symptom improvement, after six weeks, she again complained of a low-grade fever and abdominal pain, whereas the CD-related symptoms did not worsen. Contrast-enhanced computed tomography revealed thoracoabdominal aortitis, and we therefore started treatment with prednisolone, which immediately improved the fever and abdominal pain. We subsequently tapered the dose of prednisolone and resumed the administration of ADA in order to maintain the CD remission. No further episodes of aortitis relapse were noted after restarting ADA, and the CD currently remains in remission. This is the first report of the onset of aortitis during ADA therapy for CD.

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Polarization diversity of human CD4+ stem cell memory T cells

Takeshita M., Suzuki K., Kassai Y., Takiguchi M., Nakayama Y., Otomo Y., Morita R., Miyazaki T., Yoshimura A., Takeuchi T.

Clinical Immunology （Clinical Immunology） 159 （ 1 ） 107 - 117 2015年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1521-6616

© 2015 Elsevier Inc. T cells are considered to develop through three stages, from naïve T (Tn) into central memory T (Tcm) and finally into effector memory T (Tem). Among the subsets of Tn, stem cell memory T (Tscm) were recently found to be the least developed memory subset. While this subset was revealed to possess self-reproducibility and multipotentiality, little is known about the relationship between development and polarity. We conducted transcriptome analysis of human CD4+ T subsets and found that Tscm was a clearly distinct subset, located between Tn and Tcm. Surface antigen analysis and differentiation assay showed that the flexibility of polarity and the cytokine production progressively changed as the differentiation of CD4+ T cells advanced. Interestingly, we found that most cells of the CD45RO-CCR7+CCR6+ subset, hitherto considered the naïve precursor of Th17, were in fact Tscm. These findings may advance our understanding of the highly heterogeneous human helper T cells.

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Trend of patient characteristics and its impact on the response to adalimumab in patients with rheumatoid arthritis: Post hoc time-course analysis of an all-case pms in Japan

Yamanaka H., Harigai M., Ishiguro N., Inokuma S., Takei S., Takeuchi T., Tanaka Y., Suzuki H., Shinmura Y., Koike T.

Modern Rheumatology （Modern Rheumatology） 25 （ 4 ） 495 - 502 2015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 investigate the relationship between changes in patient characteristics over time and the eff ectiveness and safety of adalimumab in the treatment of rheumatoid arthritis (RA) in clinical practice. Methods. Patients enrolled in the post-marketing registry study in Japan were divided into 5 subgroups based on the time adalimumab treatment was initiated. Demographic and baseline characteristics and responses to adalimumab were compared among the 5 subgroups to detect any time-course trend. Multiple logistic regression analysis was performed to identify characteristics that were signifi cantly associated with the eff ectiveness or safety of adalimumab and to estimate response rates and the incidence of adverse drug reactions in individual subgroups. Results. During the study period, patient characteristics changed signifi cantly over time, in particular with regard to prior biologic use and concomitant methotrexate therapy. There was a signifi cant trend toward higher response rates and lower incidence of infections and injection-site reactions in patients initiating adalimumab later in the study. Patient characteristics, such as concomitant methotrexate therapy and early stage RA, were signifi cant predictors of the eff ectiveness and safety of adalimumab. Conclusions. Patient characteristics have changed since adalimumab became available for the treatment of RA; several of these characteristics were signifi cant predictors of adalimumab eff ectiveness and safety.

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Effi cacy and safety of tofacitinib as monotherapy in japanese patients with active rheumatoid arthritis: A 12-week, randomized, phase 2 study

Tanaka Y., Takeuchi T., Yamanaka H., Nakamura H., Toyoizumi S., Zwillich S.

Modern Rheumatology （Modern Rheumatology） 25 （ 4 ） 514 - 521 2015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 evaluate oral tofacitinib versus placebo for treatment of active rheumatoid arthritis in Japanese patients with inadequate response to disease-modifying antirheumatic drugs. Methods. In this double-blind, placebo-controlled, randomized, parallel-group, 12-week, phase 2 study (clinicaltrials.gov NCT00687193), 317 patients received tofacitinib: 1, 3, 5, 10, or 15 mg as monotherapy or placebo twice daily (BID). Primary endpoint: response rate by American College of Rheumatology (ACR) > 20% improvement criteria (ACR20) at week 12. Results. ACR20 response rates: 37.7% (20/53), 67.9% (36/53), 73.1% (38/52), 84.9% (45/53), and 90.7% (49/54) with tofacitinib: 1, 3, 5, 10, and 15 mg BID, respectively, versus 15.4% (8/52) with placebo (p<0.01; all doses). Dose-dependent ACR20 responses with tofacitinib versus placebo occurred from week 2 onward (p< 0.05). Changes from baseline in 28-joint disease activity score using erythrocyte sedimentation rate improved with tofacitinib versus placebo from week 4 (p < 0.01; all doses). Six tofacitinib patients experienced treatment-related serious adverse events (AEs). Most common treatment-emergent AEs: nasopharyngitis (10% vs 12%) and hyperlipidemia (5% vs 0%). Serum creatinine, hemoglobin, and total-, low-, and high-density lipoprotein-choles-terol levels increased with tofacitinib. Conclusions. Tofacitinib produced dose-dependent ACR20 responses and reduced disease activity. The safety profi le was consistent with that reported from global monotherapy trials.

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Acute kidney injury due to renal sarcoidosis during etanercept therapy: A case report and literature review

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

Internal Medicine （Internal Medicine） 54 （ 9 ） 1131 - 1134 2015年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0918-2918

© 2015 The Japanese Society of Internal Medicine. We herein report a case of renal sarcoidosis presenting as acute kidney injury (AKI) during treatment with etanercept for rheumatoid arthritis. Blood tests showed a high level of angiotensin-converting enzyme and a renal biopsy demonstrated non-caseating granulomatous tubulointerstitial nephritis. The administration of high-dose steroid therapy (1 mg/kg) and discontinuation of etanercept resulted in an improvement in the patient’s renal function. Although renal sarcoidosis induced by anti-tumor necrosis factor (TNF) therapy is an extremely rare manifestation, this case suggests that renal sarcoidosis should be considered in the differential diagnosis of AKI in patients receiving anti-TNF therapy, as providing an early diagnosis and treatment is important for preventing irreversible renal impairment.

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The effect of tocilizumab on preventing relapses in adult-onset still's disease: A retrospective, single-center study

Nishina N., Kaneko Y., Kameda H., Takeuchi T.

Modern Rheumatology （Modern Rheumatology） 25 （ 3 ） 401 - 404 2015年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2014 Japan College of Rheumatology. Objectives. To investigate the clinical effectiveness of tocilizumab (TCZ), a monoclonal antibody against the interleukin-6 receptor, in preventing relapse in patients with adult-onset Still's disease (AOSD). Methods. This retrospective study included clinical data from 40 patients who underwent regular follow-up at our institution in June 2013. Among these patients, 10 received TCZ. The relapse-free rate was analyzed by the Kaplan-Meier method. Results. The age at disease onset (median, interquartile range [IQR]) was 39 (29-52) years. The duration of disease in June 2013 (median, IQR) was 86 (41-193) months. A total of 87 relapses were documented in 27 patients. Ten patients with refractory or relapsing disease received 8 mg/kg of TCZ every 2-4 weeks. After 6 months of TCZ treatment, the median levels of C-reactive protein significantly decreased from 6.3 to 0.01 mg/dl (p < 0.01). Among these 10 patients, 11 relapses were observed before TCZ treatment, and none were observed after the treatment. The relapse-free rate of the 10 patients after starting TCZ was significantly higher than that of all 40 patients after the initial treatments (100% and 67% at 12 months, respectively; p = 0.03). Conclusions.TCZ effectively prevented relapses of AOSD, and it resolved the disease activity.

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Anti-citrullinated peptide/protein antibody (ACPA)-negative RA shares a large proportion of susceptibility loci with ACPA-positive RA: A meta-analysis of genome-wide association study in a Japanese population

Terao C., Ohmura K., Kochi Y., Ikari K., Okada Y., Shimizu M., Nishina N., Suzuki A., Myouzen K., Kawaguchi T., Takahashi M., Takasugi K., Murasawa A., Mizuki S., Iwahashi M., Funahashi K., Natsumeda M., Furu M., Hashimoto M., Ito H., Fujii T., Ezawa K., Matsubara T., Takeuchi T., Kubo M., Yamada R., Taniguchi A., Yamanaka H., Momohara S., Yamamoto K., Mimori T., Matsuda F.

Arthritis Research and Therapy （Arthritis Research and Therapy） 17 （ 1 ） 2015年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1478-6354

© Terao et al.; licensee BioMed Central. Introduction: Although susceptibility genes for anti-citrullinated peptide/protein antibodies (ACPA)-positive rheumatoid arthritis (RA) have been successfully discovered by genome-wide association studies (GWAS), little is known about the genetic background of ACPA-negative RA. We intended to elucidate genetic background of ACPA-negative RA. Method: We performed a meta-analysis of GWAS comprising 670 ACPA-negative RA and 16,891 controls for 1,948,138 markers, followed by a replication study of the top 35 single nucleotide polymorphisms (SNPs) using 916 cases and 3,764 controls. Inverse-variance method was applied to assess overall effects. To assess overlap of susceptibility loci between ACPA-positive and -negative RA, odds ratios (ORs) of the 21 susceptibility markers to RA in Japanese were compared between the two subsets. In addition, SNPs were stratified by the p-values in GWAS meta-analysis for either ACPA-positive RA or ACPA-negative RA to address the question whether weakly-associated genes were also shared. The correlations between ACPA-positive RA and the subpopulations of ACPA-negative RA (rheumatoid factor (RF)-positive and RF-negative subsets) were also addressed. Results: Rs6904716 in LEMD2 of the human leukocyte antigen (HLA) locus showed a borderline association with ACPA-negative RA (overall p = 5.7 × 10-8), followed by rs6986423 in CSMD1 (p = 2.4 × 10-6) and rs17727339 in FCRL3 (p = 1.4 × 10-5). ACPA-negative RA showed significant correlations of ORs with ACPA-positive RA for the 21 susceptibility SNPs and non-HLA SNPs with p-values far from significance. These significant correlations with ACPA-positive RA were true for ACPA-negative RF-positive and ACPA-negative RF-negative RA. On the contrary, positive correlations were not observed between the ACPA-negative two subpopulations. Conclusion: Many of the susceptibility loci were shared between ACPA-positive and -negative RA.

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Prediction of clinical response after 1 year of infliximab therapy in rheumatoid arthritis based on disease activity at 3 months: Posthoc analysis of the RISING study

Takeuchi T., Miyasaka N., Inui T., Yano T., Yoshinari T., Abe T., Koike T.

Journal of Rheumatology （Journal of Rheumatology） 42 （ 4 ） 599 - 607 2015年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

Objective. To investigate the probability of clinical remission (REM) or low disease activity (LDA) after 1 year of infliximab (IFX) therapy based on disease activity at 3 months in patients with rheumatoid arthritis (RA). Methods. Methotrexate-refractory patients with RA received 3 mg/kg of IFX at weeks 0, 2, and 6, followed by 3 mg/kg, 6 mg/kg, or 10 mg/kg every 8 weeks from Week 14 (W14) to Week 46. Correlation of disease activity at W14 with disease activity at W54 and probability of REM/LDA at W54 were analyzed in each dosing group. Results. Disease activities at W14 were significantly correlated with both disease activity at W54 and probability of REM/LDA at W54 in patients continuing 3 mg/kg as well as in those receiving 6 mg/kg or 10 mg/kg therapy from W14. Results showed that, if approximate REM or LDA had not been achieved by W14, ≥ 50% of patients continuing 3 mg/kg therapy would not be able to achieve REMor LDAatW54. However, even in patients with high or moderate disease activity atW14, dose escalation to 6 mg/kg or 10 mg/kg enabled many to achieve REM/LDA. Conclusion. Disease activity at W14 in standard-dose IFX therapy enabled the prediction of longterm clinical response at continued standard dose, as well as subsequent escalated-dose regimens. Disease activity at W14 was hypothesized to be an important index for IFX treatment strategy.

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Head-to-head comparison of the safety of tocilizumab and tumor necrosis factor inhibitors in rheumatoid arthritis patients (RA) in clinical practice: Results from the registry of Japanese RA patients on biologics for long-term safety (REAL) registry

Sakai R., Cho S., Nanki T., Watanabe K., Yamazaki H., Tanaka M., Koike R., Tanaka Y., Saito K., Hirata S., Amano K., Nagasawa H., Sumida T., Hayashi T., Sugihara T., Dobashi H., Yasuda S., Sawada T., Ezawa K., Ueda A., Fujii T., Migita K., Miyasaka N., Harigai M., Atsumi T., Ishigatsubo Y., Ihata A., Mimori T., Takasaki Y., Tamura N., Hashiramoto A., Shiozawa S., Kameda H., Kaneko Y., Takeuchi T., Ochi S., Miura Y., Nonomura Y., Nakajima A., Michishita K., Yamamoto K., Ueki Y., Nagasaka K., Okada A., Kawakami A., Tohma S., Nakajima A., Yamanaka H.

Arthritis Research and Therapy （Arthritis Research and Therapy） 17 （ 1 ） 2015年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1478-6354

© Sakai et al. Introduction: The objective of this study was to directly compare the safety of tocilizumab (TCZ) and TNF inhibitors (TNFIs) in rheumatoid arthritis (RA) patients in clinical practice. Methods: This prospective cohort study included RA patients starting TCZ [TCZ group, n = 302, 224.68 patient-years (PY)] or TNFIs [TNFI group, n = 304, 231.01 PY] from 2008 to 2011 in the registry of Japanese RA patients on biologics for long-term safety registry. We assessed types and incidence rates (IRs) of serious adverse events (SAEs) and serious infections (SIs) during the first year of treatment. Risks of the biologics for SAEs or SIs were calculated using the Cox regression hazard analysis. Results: Patients in the TCZ group had longer disease duration (P <0.001), higher disease activity (P = 0.019) and more frequently used concomitant corticosteroids (P <0.001) than those in the TNFI group. The crude IR (/100 PY) of SIs [TCZ 10.68 vs. TNFI 3.03; IR ratio (95% confidence interval [CI]), 3.53 (1.52 to 8.18)], but not SAEs [21.36 vs. 14.72; 1.45 (0.94 to 2.25)], was significantly higher in the TCZ group compared with the TNFI group. However, after adjusting for covariates using the Cox regression hazard analysis, treatment with TCZ was not associated with higher risk for SAEs [hazard ratio (HR) 1.28, 95% CI 0.75 to 2.19] or SIs (HR 2.23, 95% CI 0.93 to 5.37). Conclusions: The adjusted risks for SAEs and SIs were not significantly different between TCZ and TNFIs, indicating an influence of clinical characteristics of the patients on the safety profile of the biologics in clinical practice.

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Pharmacokinetics, efficacy and safety profiles of etanercept monotherapy in Japanese patients with rheumatoid arthritis: Review of seven clinical trials

Takeuchi T., Miyasaka N., Kawai S., Sugiyama N., Yuasa H., Yamashita N., Sugiyama N., Wagerle L., Vlahos B., Wajdula J.

Modern Rheumatology （Modern Rheumatology） 25 （ 2 ） 173 - 186 2015年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Ó 2014 Japan College of Rheumatology. Conventional synthetic disease-modifying anti-rheumatic drugs, including methotrexate, may not be tolerated by all patients with rheumatoid arthritis (RA), and limited international data for etanercept (ETN) monotherapy are available. The aim of this review was to summarize the clinical program for ETN monotherapy in Japanese patients with RA, which has included a pharmacokinetic study, clinical trials for registration, long-term studies, and once-weekly dosing studies. Pharmacokinetic results showed that serum concentrations of ETN were linear with dose levels and were similar to other international studies. Across interventional studies, 652 Japanese patients with active RA were treated with ETN. In the registration studies, ETN treatment led to consistent improvement in American College of Rheumatology 20/50/70 scores, European League Against Rheumatism Good Response, Disease Activity Score 28 erythrocyte sedimentation rate remission, and Health Assessment Questionnaire disability index. In the long-term studies, efficacy was maintained for up to 180 weeks. Similar results were seen in the once-weekly studies. Across the studies, more than 870 patient-years of exposure to ETN were recorded. Discontinuations owing to lack of efficacy or adverse events were modest and no new safety signals were recorded. These studies demonstrated that ETN monotherapy is efficacious and well-tolerated in Japanese patients with RA.

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