論文 - 竹内　勤

Predictors of favorable responses to immunosuppressive treatment in pulmonary arterial hypertension associated with connective tissue disease

Yasuoka Hidekata, Shirai Yuichiro, Tamura Yuichi, Takeuchi Tsutomu, Kuwana Masataka

Circulation Journal 82 （ 2 ） 546 - 554 2018年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1346-9843

　概要を見る

<p>Background: The potential efficacy of immunosuppressive (IS) treatment has been reported in patients with pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD), but its positioning in the treatment algorithm remains uncertain. The aim of this study was to identify predictors of favorable responses to first-line IS treatment. Methods and Results: This single-center retrospective study included 30 patients with PAH accompanied by systemic lupus erythematosus (SLE), mixed CTD (MCTD), or primary Sjögren’s syndrome (SS) who received first-line IS treatment alone or in combination with pulmonary vasodilators. When short-term treatment response was defined as an improvement in World Health Organization functional class at 3 months, 16 patients (53%) were short-term responders. Simultaneous diagnosis of PAH and CTD, and the use of immunosuppressants, especially intravenous cyclophosphamide, in addition to glucocorticoids were identified as independent predictors of a short-term response (P=0.004 and 0.0002, respectively). Cumulative rates free of PAH-related death were better in short-term responders than non-responders (P=0.04), and were best in patients with a simultaneous diagnosis of PAH and CTD who were treated initially with a combination of glucocorticoids and immunosuppressants. Conclusions: Patients with a simultaneous diagnosis of PAH and CTD, including SLE, MCTD, and primary SS, should receive intensive IS treatment regimens to achieve better short- and long-term outcomes.</p>

• Access to Document (DOI)

Tendonitis on the fingers in Behçet’s disease

Matsumoto Kotaro, Kaneko Yuko, Takeuchi Tsutomu

Internal Medicine 57 （ 17 ）  2018年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0918-2918

• Access to Document (DOI)

Safety, pharmacokinetics, and efficacy of E6011, an antifractalkine monoclonal antibody, in a first-in-patient phase 1/2 study on rheumatoid arthritis

Tanaka Y., Takeuchi T., Umehara H., Nanki T., Yasuda N., Tago F., Kawakubo M., Kitahara Y., Hojo S., Kawano T., Imai T.

Modern Rheumatology （Modern Rheumatology）  28 （ 1 ） 58 - 65 2018年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1439-7595

　概要を見る

© 2017 Japan College of Rheumatology. Objective: Fractalkine (CX3CL1/FKN) is a chemokine that regulates chemotaxis and adhesion of CX3C chemokine receptor 1 (CX3CR1)-expressing inflammatory cells. We conducted the first phase 1/2, open-label, multiple ascending dose study of E6011, a humanized anti-FKN monoclonal antibody, in Japanese rheumatoid arthritis (RA) patients (clinicaltrial.gov identifier: NCT02196558). Methods: Active RA patients with an inadequate response or intolerance to methotrexate or tumor necrosis factor (TNF) inhibitor received E6011 at week 0, 1, 2, and thereafter every 2 weeks for 12 weeks. Results: Twelve, 15, and 10 subjects were enrolled in the 100, 200, and 400 mg cohorts, respectively. No severe adverse events (AEs) or deaths occurred, and no major differences were observed in the incidence or severity of AEs across the cohorts. Serum E6011 concentrations increased dose dependently. American College of Rheumatology (ACR) 20, 50, and 70 responses at week 12 were 75.0%, 33.3%, and 8.3% in the 100 mg cohort; 66.7%, 20.0%, and 13.3% in the 200 mg cohort; and 60.0%, 30.0%, and 20.0% in the 400 mg cohort, respectively. Conclusions: E6011 appeared to be safe and well tolerated in RA patients during this 12-week treatment period, suggesting that E6011 has an effective clinical response in active RA patients.

• Access to Document (DOI)

Safety and effectiveness of tacrolimus add-on therapy for rheumatoid arthritis patients without an adequate response to biological disease-modifying anti-rheumatic drugs (DMARDs): Post-marketing surveillance in Japan

Takeuchi T., Ishida K., Shiraki K., Yoshiyasu T.

Modern Rheumatology （Modern Rheumatology）  28 （ 1 ） 48 - 57 2018年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1439-7595

　概要を見る

© 2017 Japan College of Rheumatology. Published by Informa UK Limited, trading as Taylor & Francis Group. Objectives: Post-marketing surveillance (PMS) was conducted to assess the safety and effectiveness of tacrolimus (TAC) add-on therapy for patients with rheumatoid arthritis (RA) and an inadequate response to biological disease-modifying anti-rheumatic drugs (DMARDs). Methods: Patients with RA from 180 medical sites across Japan were registered centrally with an electronic investigation system. The observational period was 24 weeks from the first day of TAC administration concomitantly with biological DMARDs. Results: Safety and effectiveness populations included 624 and 566 patients, respectively. Patients were predominantly female (81.1%), with a mean age of 61.9 years. Overall, 125 adverse drug reactions (ADRs) occurred in 94 patients (15.1%), and 15 serious ADRs occurred in 11 patients (1.8%). These incidences were lower compared with previously reported incidences after TAC treatment in PMS, and all of the observed ADRs were already known. A statistically significant improvement was observed in the primary effectiveness variable of Simplified Disease Activity Index after TAC treatment; 62.7% of patients achieved remission or low disease activity at week 24. Conclusions: TAC is well tolerated and effective when used as an add-on to biological DMARDs in Japanese patients with RA who do not achieve an adequate response to biological DMARDs in a real-world clinical setting.

• Access to Document (DOI)

Post-marketing surveillance study of the long-term use of mizoribine for the treatment of lupus nephritis: 2-Year results

Takeuchi T., Okada K., Yoshida H., Yagi N.

Modern Rheumatology （Modern Rheumatology）  28 （ 1 ） 85 - 94 2018年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1439-7595

　概要を見る

© 2017 Japan College of Rheumatology. Published by Informa UK Limited, trading as Taylor & Francis Group. Objectives: To understand the status of mizoribine use in patients with lupus nephritis (LN) and to collect safety- and efficacy-related data on 2-year treatment with mizoribine. Methods: A continuous survey was conducted between March 2010 and July 2015. Results: The analysis set included 559 patients (mean age 39.5 years, females 82.6%, mean duration of systemic lupus erythematosus (SLE) 8.4 years, mean duration of LN 5.9 years). Renal function was satisfactory for 6 months, but worsened from 12 months, with significant worsening at 24 months. By the ACR 2006 remission criteria (eGFR >60), at 24 months, 26.5% of patients achieved complete remission, and 63.3% achieved complete or partial remission. The urine protein to creatinine ratio decreased significantly. The SLE Disease Activity Index 2000 score decreased significantly at 12 and 24 months. Overall, 98 (17.5%) patients experienced 124 adverse drug reactions (ADRs); 3.6% experienced serious ADRs. Mizoribine was used with a steroid in 99.3% and an immunosuppressant in 51.2%; tacrolimus was used in 43.8%. The oral steroid dosage decreased from baseline to 24 months. The incidence of ADRs was not significantly different with concomitant tacrolimus use. Conclusions: The results suggest that long-term mizoribine is safe and effective, even when used with tacrolimus.

• Access to Document (DOI)

Economic impact of adalimumab treatment in Japanese patients with rheumatoid arthritis from the adalimumab non-interventional trial for up-verified effects and utility (ANOUVEAU) study

Tanaka Y., Yamazaki K., Nakajima R., Komatsu S., Igarashi A., Tango T., Takeuchi T.

Modern Rheumatology （Modern Rheumatology）  28 （ 1 ） 39 - 47 2018年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1439-7595

　概要を見る

© 2017 Japan College of Rheumatology. Objectives: The objective of this study is to evaluate the economic impact of adalimumab (ADA) on Japanese rheumatoid arthritis (RA) patients. Methods: ANOUVEAU was a 48-week multicenter, prospective, observational, single-cohort study. Work-related outcomes including absenteeism, presenteeism, overall work impairment (OWI), and activity impairment (AI) were evaluated using the RA-related work productivity and activity impairment (WPAI/RA). The amount of productivity loss was estimated via multiplication of absenteeism, presenteeism and OWI by the national average occupational wage for paid worker (PW) and part time worker (PTW), and via multiplication of AI by the estimated wage for domestic work for home maker (HM). Results: In this analysis, 1196 patients were included. At week 48, measures of productivity loss due to absenteeism, presenteeism, OWI, and AI were significantly improved by administrating ADA to RA patients in all employment types (PW, PTW, and HM), compared to baseline (p <.01). Productivity loss of Japanese society by RA disease was estimated to be $9.80 billion. The annual decrease in productivity loss through ADA administration to Japanese RA patients was estimated to be $3.76 billion. Conclusions: The socioeconomic burden of RA is high, but ADA treatment may reduce productivity loss related to RA.

• Access to Document (DOI)

Biomarkers as a treatment guide in rheumatoid arthritis

Takeuchi T.

Clinical Immunology （Clinical Immunology）  186   59 - 62 2018年01月

研究論文（学術雑誌）, 査読有り,  ISSN  15216616

　概要を見る

© 2017 Elsevier Inc. It is anticipated that biomarkers support rheumatologists to judge a group of patients that can improve the diagnosis and prognosis, and further facilitate appropriate and precise treatment with targeted therapy. In particular, biomarkers for predicting and monitoring response to biological disease modifying anti-rheumatic drugs (DMARDs) are demanding. Given the mechanism action of biological DMARDs is much more simple than the conventional synthetic DMARDs, a variety of approaches to find such biomarkers has been taken recent years. In this article, I will summarize the background for biomarker research and introduce recent topics in the research and the possible clinical applications of biomarkers to guide treatment in rheumatoid arthritis (RA).

• Access to Document (DOI)

[Diagnosis and treatment of rheumatoid arthritis:toward the best practice. Towards precision medicine in rheumatoid arthritis.]

Suzuki K, Takeuchi T

Clinical calcium 28 （ 5 ） 626 - 629 2018年

研究論文（学術雑誌）, 査読有り,  ISSN  0917-5857

• Access to Document (DOI)

Serum soluble interleukin-2 receptor is a useful biomarker for disease activity but not for differential diagnosis in IgG4-related disease and primary Sjogren's syndrome adults from a defined population

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

CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 36 （ 3 ） S157 - S164 2018年

研究論文（学術雑誌）, 査読有り,  ISSN  0392-856X

Safety profile of baricitinib for the treatment of rheumatoid arthritis up to 5.5 years: an updated integrated safety analysis

Genovese M., Smolen J., Takeuchi T., Hyslop D., Macias W., Rooney T., Chen L., Dickson C., Riddle J., Cardillo T., Ishii T., Winthrop K., Larsson E.

SCANDINAVIAN JOURNAL OF RHEUMATOLOGY 47   35 - 35 2018年

研究論文（学術雑誌）, 査読有り,  ISSN  0300-9742

Clinical and immunological features of anti-centromere antibody-positive primary Sjogren's syndrome

Tsukamoto Masako, Suzuki Katsuya, Takeuchi Tsutomu

CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 36 （ 3 ） S282 - S282 2018年

研究論文（学術雑誌）, 査読有り,  ISSN  0392-856X

Increased circulating CD14(bright)CD16(+) intermediate monocytes are regulated by TNF-alpha and IL-6 axis in accordance with disease activity in patients with rheumatoid arthritis

Tsukamoto Masako, Suzuki Katsuya, Seta Noriyuki, Takeuchi Tsutomu

CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 36 （ 4 ） 540 - 544 2018年

研究論文（学術雑誌）, 査読有り,  ISSN  0392-856X

Factors predicting the therapeutic response to methotrexate in Japanese patients with rheumatoid arthritis: A hospital-based cohort study

Hakamata J., Kaneko Y., Shimizu M., Yamaoka K., Maruyama J., Takeuchi T., Mochizuki M., Hashiguchi M.

Biological and Pharmaceutical Bulletin （Biological and Pharmaceutical Bulletin）  41 （ 9 ） 1414 - 1422 2018年

研究論文（学術雑誌）, 査読有り,  ISSN  09186158

　概要を見る

© 2018 The Pharmaceutical Society of Japan. Methotrexate (MTX) is used widely as a first-line drug for the treatment of rheumatoid arthritis (RA) worldwide. There are large interindividual differences in the therapeutic response to MTX, but it is not known which factors influence them. We therefore investigated predictive factors associated with the therapeutic response to MTX in a hospital-based cohort study. Japanese adult RA outpatients prescribed MTX were enrolled and their characteristics were collected from the electronic medical records. The European League Against Rheumatism (EULAR) response criteria were used as the response to MTX therapy. The observation period was 1 year after beginning MTX administration. Sixteen types of single-nucleotide polymorphisms were investigated using the real-time PCR method. Associations between the MTX response and patient characteristics were evaluated using the multivariate logistic regression model. Among 70 Japanese adult RA outpatients, 52 were classified as MTX responders. In multivariate analysis, patients with the solute carrier family 19 member 1 (SLC19A1) 80G>A A/A genotype had a better response than those with the A/G or G/G genotype, and patients with the C allele of γ-glutamyl hydrolase (GGH) 16T>C had a better response than those with the T/T genotype.This study showed that the therapeutic response to MTX in Japanese RA patients was associated with the genetic polymorphisms of SLC19A1 80G>A and GGH 16T>C in actual clinical practice.

• Access to Document (DOI)

Discovery of drug candidates for primary Sjogren's syndrome that target a BAFF receptor

Yoshimoto Keiko, Suzuki Katsuya, Seta Noriyasu, Sugahara Kunio, Chiba Kenji, Takeuchi Tsutomu

CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 36 （ 3 ） S283 - S283 2018年

研究論文（学術雑誌）, 査読有り,  ISSN  0392-856X

Clinical efficacy, radiographic, and safety results of golimumab monotherapy in Japanese patients with active rheumatoid arthritis despite prior therapy with disease-modifying antirheumatic drugs: Final results of the GO-MONO trial through week 120

竹内 勤

Modern Rheumatology （Modern Rheumatology）  28 （ 5 ） 770 - 779 2017年12月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  14397595

　概要を見る

© 2017, © 2017 Japan College of Rheumatology. Published by Informa UK Limited, trading as Taylor & Francis Group. Objective: Evaluate the safety and efficacy of golimumab through week 120 in Japanese patients with active rheumatoid arthritis (RA) previously treated with DMARDs. Methods: Japanese patients with active RA despite prior DMARDs were randomized to placebo (Group 1, n = 105), golimumab 50 mg (Group 2, n = 101), or golimumab 100 mg (Group 3, n = 102). At week 16, Group 1 patients crossed over to golimumab 50mg; after week 52, a one-time golimumab dose reduction from 100 to 50 mg was permitted. Assessments included ACR20/50/70 responses and good/moderate DAS28-ESR responses. Radiographic progression was assessed with the van der Heijde-modified Sharp (vdH-S) score. Safety and efficacy were assessed through week 120. Results: ACR20 response rates at week 52 in Group 1, Group 2, and Group 3 were 70.6%, 71.4%, and 81.9%, respectively, and maintained through week 104 (87.2%, 85.1%, 88.9%, respectively) and week 120 (86.1%, 87.0%, 89.5%, respectively). Similar trends were observed for ACR50, ACR 70, and DAS28-ESR. Median change in total vdH-S at weeks 52, 104, and 120 ranged from 0.0 to 1.5 across treatment groups. Through week 120, 93.8%/97.1% had an AE with golimumab 50 mg/100 mg, respectively, and 19.7%/11.8% had an SAE. Infections were the most common AE. Conclusion: Clinical response to golimumab 50 mg and 100 mg was maintained over 2 years in Japanese patients with active RA despite prior DMARDs.

• Access to Document (DOI)

Serum soluble interleukin-2 receptor is a useful biomarker for disease activity in IgG4-related disease and primary Sjogren’s syndrome

竹内 勤

Clinical Experimental Rheumatology 2017年12月

研究論文（学術雑誌）, 共著, 査読有り

Polymyositis with elevated serum IgG4 levels and abundant IgG4 + plasma cell infiltration

Anan R., Akiyama M., Kaneko Y., Kikuchi J., Suzuki K., Matsubara S., Takeuchi T.

Medicine (United States) （Medicine (United States)）  96 （ 48 ）  2017年12月

研究論文（学術雑誌）, 査読有り,  ISSN  00257974

　概要を見る

Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc. Introduction: Polymyositis (PM) is a type of autoimmune, inflammatory myopathy. IgG4-related disease (IgG4-RD) is a recently recognized disease entity characterized by elevated serum IgG4 levels and IgG4 + plasma-cell infiltration of various organs. However, several reports have described cases of other diseases that present with those features, suggesting the importance of careful differential diagnosis. Herein, we report the first case of PM with elevated serum IgG4 levels and IgG4 + plasma cells in the muscles, mimicking IgG4-RD. A 73-year-old woman visited our hospital because of proximal muscle weakness of both thighs. Her blood test showed high levels of serum creatinine kinase, aldolase, and IgG4. Magnetic resonance imaging of the thighs showed muscle edema. Needle electromyography showed findings typical of myositis. Histological analysis of her left quadriceps revealed infiltration of IgG4 + plasma cells as well as CD8 + T cells. Scattered necrotic and regenerating muscle fibers with no specific findings for IgG4-RD (storiform fibrosis and obliterative phlebitis) were typical for PM. We diagnosed her condition as PM and treated her with 40 mg/day of prednisolone that decreased levels of muscle enzymes and improved muscle weakness. Conclusion: Our case indicated that PM could present with high serum IgG4 levels and IgG4 + plasma-cell infiltration, mimicking IgG4-RD. Although the mechanism of IgG4 elevation in such PM is unclear, our case highlights the necessity to recognize that high serum IgG4 levels and IgG4 + plasma-cell infiltration in organs are not specific for IgG4-RD.

• Access to Document (DOI)

Genome-wide Association Study of Idiopathic Osteonecrosis of the Femoral Head

Sakamoto Y., Yamamoto T., Sugano N., Takahashi D., Watanabe T., Atsumi T., Nakamura J., Hasegawa Y., Akashi K., Narita I., Miyamoto T., Takeuchi T., Ikari K., Amano K., Fujie A., Kubo T., Tada Y., Kaneuji A., Nakamura H., Miyamura T., Kabata T., Yamaji K., Okawa T., Sudo A., Ohzono K., Tanaka Y., Yasunaga Y., Matsuda S., Imai Y., Nakashima Y., Motomura G., Ikemura S., Yamaguchi R., Karasuyama K., Sonoda K., Nishii T., Sakai T., Takao M., Irie T., Asano T., Iwasaki N., Atsumi T., Tamaoki S., Nakanishi R., Tanabe S., Kishida S., Hagiwara S., Seki T., Tsukamoto H., Niiro H., Arinobu Y., Akahoshi M., Mitoma H., Ayano M., Kuroda T., Toyama Y., Funayama A., Hanaoka H., Yamaoka K., Kawaguchi Y., Yamanaka H., Hosozawa T., Momohara S., Chino K., Fujioka M., Ueshima K., Ishida M., Saito M., Hayashi S., Ikegami A., Ichiseki T., Mizokawa S., Ohta Y., Kajino Y., Sekiya F., Higuchi F., Hasegawa M., Miyamoto N., Miyazaki S., Yamaguchi T., Ando W., Saito K., Nakano K., Kuroda Y., Yamasaki T., Akiyama M., Kubo M., Kamatani Y., Iwamoto Y., Ikegawa S.

Scientific Reports （Scientific Reports）  7 （ 1 ）  2017年12月

研究論文（学術雑誌）, 査読有り

　概要を見る

© 2017 The Author(s). Idiopathic osteonecrosis of the femoral head (IONFH) is an ischemic disorder that causes bone necrosis of the femoral head, resulting in hip joint dysfunction. IONFH is a polygenic disease and steroid and alcohol have already known to increase its risk; however, the mechanism of IONFH remains to be elucidated. We performed a genome-wide association study using ~60,000 subjects and found two novel loci on chromosome 20q12 and 12q24. Big data analyses identified LINC01370 as a candidate susceptibility gene in the 20q12 locus. Stratified analysis by IONFH risk factors suggested that the 12q24 locus was associated with IONFH through drinking capacity. Our findings would shed new light on pathophysiology of IONFH.

• Access to Document (DOI)

Remission induction by Raising the dose of Remicade in RA (RRRR) study: Rationale and study protocol for a randomized controlled trial comparing for sustained clinical remission after discontinuation of infliximab in patients with rheumatoid arthritis

Oba K., Horie N., Sato N., Saito K., Takeuchi T., Mimori T., Miyasaka N., Koike T., Tanaka Y.

Contemporary Clinical Trials Communications （Contemporary Clinical Trials Communications）  8   49 - 54 2017年12月

研究論文（学術雑誌）, 査読有り,  ISSN  24518654

　概要を見る

© 2017 The Authors Infliximab, an inhibitor of TNF-α, is one of the most widely used biological disease-modifying antirheumatic drugs. Recent studies indicated that baseline serum TNF-α could be considered as a key indicator for optimal dosing of infliximab for RA treatment to achieve the clinical response and its sustained remission. The Remission induction by Raising the dose of Remicade in RA (RRRR) study is an open-label, parallel group, multicenter randomized controlled trial to compare the proportions of clinical remission based on the simplified disease activity index (SDAI) after 1 year of treatment and its sustained remission rate after another 1 year between the investigational treatment strategy (for which the dose of infliximab was chosen based on the baseline serum TNF) and the standard strategy of 3 mg/kg per 8 weeks of infliximab administration in infliximab-naïve patients with RA showing an inadequate response to MTX. The primary endpoint is the proportion of patients who kept discontinuation of infliximab 1 year after discontinued infliximab at the time of 54 weeks after the first administration of infliximab. The secondary endpoints are the proportion of clinical remission based on SDAI and changes in SDAI from baseline at each time point, other clinical parameters, quality of life measures and adverse events. Target sample size of randomized patients is 400 patients in total. The main results of the RRRR study are expected to be published at the end of 2017.

• Access to Document (DOI)

Efficacy and safety of baricitinib in Japanese patients with rheumatoid arthritis: Subgroup analysis of four multinational phase 3 randomized trials

竹内 勤

Modern Rheumatology 2017年11月

研究論文（学術雑誌）, 共著, 査読有り