論文 - 竹内　勤

Involvement of αEβ7 (CD103) in the pathogenesis of autoimmune diseases

Yoshimoto K., Kurasawa T., Suzuki K., Takeuchi T.

Japanese Journal of Clinical Immunology （Japanese Journal of Clinical Immunology）  37 （ 3 ） 171 - 175 2014年

研究論文（学術雑誌）, 査読有り,  ISSN  09114300

　概要を見る

αEβ7 (CD103), one of integrin family molecules, is a heterodimer consisting of an αE subunit and a β7 subunit. αEβ7 is expressed in several subsets of lymphocytes including T cells, intestinal intraepithelial lymphocytes and lamina propria lymphocytes. αEβ7 a ligand for E-cadherin, which is mainly expressed in epithelial cells, and an interaction between αEβ7 and E-cadherin results in adhesion of lymphocytes to epithelial cells. We found that EC5 domain, one of domains consisting E-cadherin, was indispensable for binding of E-cadherin with αEβ7. Accumulating evidence suggests that αEβ7 is not only involved in intestinal immune responses but also tissue damages associated with inflammatory diseases including autoimmune diseases. While E-cadherin is constitutively expressed in epithelial cells, the expression of αEβ7 is induced in T cells upon inflammatory stimulation in vitro. In addition, TGF-β1 induces the expression of αEβ7 via a pathway including Smad. These findings raise the possibility that αEβ7 is a potential therapeutic target for inflammatory diseases. We postulate that molecules that interfere with interaction between αEβ7 and E-cadherin are drug candidates for the diseases. We have been focusing on αEβ7 and vigorously investigating the mechanism that underlies the pathogenesis of autoimmune diseases. © 2014 The Japan Society for Clinical Immunology.

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Overview of lupus nephritis management guidelines and perspective from Asia

竹内 勤

International Journal of Rheumatic Diseases 16 （ 6 ） 625 - 636 2013年12月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1756-1841

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Intravenous epoprostenol treatment of patients with connective tissue disease and pulmonary arterial hypertension at a single center

Shirai Y., Yasuoka H., Takeuchi T., Satoh T., Kuwana M.

Modern Rheumatology （Modern Rheumatology）  23 （ 6 ） 1211 - 1220 2013年11月

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

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Objective: To assess the efficacy of epoprostenol treatment in Japanese patients with pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD). Methods: Sixteen patients with PAH-CTD treated with continuous intravenous epoprostenol at a single center between 2000 and 2009 were enrolled. Baseline characteristics, short-term and long-term outcomes, predictors of mortality, and safety profiles were evaluated. For survival analysis, 16 controls were selected who matched the underlying CTD, World Health Organization functional class, and use of PAH drugs, except for epoprostenol. Results: Six patients had systemic lupus erythematosus, five had mixed CTD, four had systemic sclerosis, and one had primary Sjögren's syndrome. The mean pulmonary arterial pressure (mPAP), cardiac index (CI), pulmonary vascular resistance, and functional class were significantly improved during the first 6 months of epoprostenol treatment. Cumulative survival rates at 1, 2, and 3 years in epoprostenol-treated patients were 69, 69, and 55 %, respectively, and were significantly better than those of the controls. Functional class, CI at baseline, and reduction of mPAP at 6 months were identified as predictors of survival. Adverse events, including flushing and catheterrelated infection, were frequent, but all patients tolerated the treatment. Conclusion: Based on the improvements in both shortterm and long-term outcomes among our patient cohort, epoprostenol is an effective treatment for CTD patients with advanced PAH. © Japan College of Rheumatology 2013.

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Prevention of joint destruction by tacrolimus in patients with early rheumatoid arthritis: A post hoc analysis of a double-blind, randomized, placebo-controlled study

Tanaka Y., Kawai S., Takeuchi T., Yamamoto K., Miyasaka N.

Modern Rheumatology （Modern Rheumatology）  23 （ 6 ） 1045 - 1052 2013年11月

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

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Objectives: A multicenter, randomized, double-blind, placebo-controlled study of the oral calcineurin inhibitor tacrolimus was performed in patients with early rheumatoid arthritis who had responded poorly to disease-modifying antirheumatic drugs (DMARDs), and factors related to suppression of joint destruction were investigated. Methods: The change in the total Sharp score (ΔTSS) was assessed by univariate analysis in patients with X-ray films to identify the main determinant of a ΔTSS of <0.5 in week 52. Patients with this factor were then investigated further. Results: Univariate analysis showed that a baseline C-reactive protein (CRP) level of <1.5 mg/dL was the major determinant of ΔTSS <0.5 at week 52 in the tacrolimus group. Detailed analysis of patients with a baseline CRP of <1.5 mg/dL revealed no significant differences in background factors between the two groups. In week 52, ΔTSS was significantly smaller in the tacrolimus group than in the placebo group (2.67 ± 5.40 vs. 8.05 ± 10.32, respectively, p = 0.017). Both groups had a similar incidence of adverse reactions. Conclusions: Adding tacrolimus to DMARDs significantly suppressed disease activity and joint destruction in patients with early rheumatoid arthritis, a disease duration B3 years, a CRP<1.5 mg/dL, and a poor response to oral DMARDs. © Japan College of Rheumatology 2012.

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Reduction of plasma IL-6 but not TNF-α by methotrexate in patients with early rheumatoid arthritis: A potential biomarker for radiographic progression

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

Clinical Rheumatology （Clinical Rheumatology）  32 （ 11 ） 1661 - 1666 2013年11月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0770-3198

　概要を見る

Objective: To determine the effect of methotrexate (MTX) on plasma levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α and to investigate their associations with clinical and radiographic responses in patients with early rheumatoid arthritis (RA). Methods: Sixty-two untreated RA patients with the disease duration of ≤36 months in whom MTX was initiated were consecutively identified in our prospective RA cohort and included in this study. Concomitant use of prednisolone and synthetic disease-modifying anti-rheumatic drugs with MTX was allowed, but patients who used biological agents were excluded. Plasma IL-6 and TNF-α levels were measured at the time of diagnosis (baseline) and 1 year later. The relationships of the clinical and radiographic data with plasma levels of IL-6 and TNF-α were analyzed. Results: The median age of the patients was 57 years, 49 patients were female, and the median disease duration was 3 months. Forty-six (74.2 %) patients were anti-cyclic citrullinated protein antibody-positive. Serum C-reactive protein (CRP), plasma IL-6, and DAS28 decreased significantly (p <0.001) after MTX treatment, but plasma TNF-α did not. Radiographic progression was significantly correlated with disease activity score and plasma IL-6 levels but not with CRP or TNF-α after MTX treatment. Patients with plasma IL-6 level above 4.03 pg/ml showed clinically relevant radiographic progression with a sensitivity of 91.7 % and a specificity of 88.0 %. Conclusion: In this early RA cohort, we demonstrated a significant (p <0.001) reduction of plasma IL-6, but not TNF-α, during MTX treatment. The post-treatment IL-6 level was a strong indicator of radiographic progression. © 2013 Clinical Rheumatology.

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Safety and effectiveness of 6 months' etanercept monotherapy and combination therapy in Japanese patients with rheumatoid arthritis: Effect of concomitant disease-modifying antirheumatic drugs

Koike T., Harigai M., Inokuma S., Ishiguro N., Ryu J., Takeuchi T., Tanaka Y., Yamanaka H., Hirose T., Yoshinaga T., Suzukawa M.

Journal of Rheumatology （Journal of Rheumatology）  40 （ 10 ） 1658 - 1668 2013年10月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0315-162X

　概要を見る

Objective. To assess real-world safety, tolerability, and effectiveness of etanercept monotherapy, etanercept plus methotrexate (MTX), or etanercept plus other disease-modifying antirheumatic drugs (DMARD) in Japanese patients with active rheumatoid arthritis (RA) despite previous treatment with DMARD. Methods. In this 24-week, all-cases postmarketing surveillance study, adverse events (AE) were coded using the Medical Dictionary for Regulatory Activities. Effectiveness was assessed every 4 weeks using the 28-joint Disease Activity Score and the European League Against Rheumatism response criteria. Results. Of 13,861 patients (81% women) in the analysis, 3616, 2506, and 7739, respectively, were classified into etanercept monotherapy (ETN-mono), etanercept plus DMARD other than MTX (ETN + DMARD), and etanercept plus MTX (ETN + MTX) groups. Rates of AE and serious AE (SAE) in the ETN + MTX group were lower than in other groups. Risk of SAE or serious infections was not significantly increased with higher versus lower MTX doses at baseline or with concomitant use of salazosulfapyridine or bucillamine in ETN + DMARD versus ETN-mono groups. A greater likelihood of achieving clinical remission was seen with ETN + MTX versus ETN-mono (OR 1.36; 95% CI, 1.16-1.60; p < 0.001). Higher MTX dose at baseline was associated with a higher remission rate (> 8 mg vs 0 to ≤ 4 mg, OR 1.47, 95% CI 1.07-2.00, p = 0.016; 6 to ≤ 8 mg vs 0 to ≤ 4 mg, OR 1.27, 95% CI 1.01-1.60, p = 0.038). Conclusion. Combination therapies with etanercept plus MTX or other DMARD were reasonably well tolerated, and ETN + MTX at higher doses was more effective than ETN-mono in Japanese patients with RA. © 2013. All rights reserved.

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Osteolytic change of distal interphalangeal joints and sacroiliac joints in subluxing arthropathy associated with anti-Jo-1 antibody

竹内 勤

Joint Bone and Spine 80 （ 5 ） 544 - 545 2013年10月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1297-319X

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Distinct Arthropaties In Patients With Anti-Aminoacyl tRNA Synthetase Antibodies: Utility Of Autoantibody Profiles In Discrimination

竹内 勤

Arthritis and Rheumatism 65   S881 - S881 2013年10月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0004-3591

Osteolytic change of distal interphalangeal joints and sacroiliac joints in subluxing arthropathy associated with anti-Jo-1 antibody.

Kaneko Yuko, Kuwana Masataka, Takeuchi Tsutomu, Oddis Chester V.

Joint, bone, spine : revue du rhumatisme 80 （ 5 ） 544 - 545 2013年10月

研究論文（学術雑誌）, 共著, 査読有り

No increased mortality in patients with rheumatoid arthritis treated with biologics: Results from the biologics register of six rheumatology institutes in Japan

Nakajima A., Saito K., Kojima T., Amano K., Yoshio T., Fukuda W., Inoue E., Taniguchi A., Momohara S., Minota S., Takeuchi T., Ishiguro N., Tanaka Y., Yamanaka H.

Modern Rheumatology （Modern Rheumatology）  23 （ 5 ） 945 - 952 2013年09月

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

　概要を見る

Objective: To investigate the influence of biologics on mortality and risk factors for death in rheumatoid arthritis (RA) patients. Methods: RA patients treated with at least one dose of biologics in daily practice in six large rheumatology institutes ("biologics cohort") were observed until 15 May 2010 or death, whichever occurred first. Mortality of the biologics cohort and the "comparator cohort" (comprising patients among the IORRA cohort who had never been treated with biologics) was compared to that of the Japanese general population. Factors associated with mortality were assessed by a Cox model. Results: Among 2683 patients with 6913.0 patient-years of observation, 38 deaths were identified in the biologics cohort. The probability of death in patients lost to follow-up, calculated using the weighted standardized mortality ratio (SMR), was 1.08 [95 % confidence interval (CI) 0.77-1.47] in the biologics cohort and 1.28 (95 % CI 1.17-1.41) in the comparator cohort. Pulmonary involvement was the main cause of death (47.4 %), and the disease-specific SMR of pneumonia was 4.19 (95 % CI 1.81-8.25). Risk factors for death included male gender [hazard ratio (HR) 2.78 (95 % CI 1.24-6.22)], advanced age (HR 1.07, 95 % CI 1.03-1.11), and corticosteroid dose (HR 1.08, 95 % CI 1.01-1.17). Conclusion: Mortality in RA patients exposed to biologics did not exceed that in patients not exposed to biologics, but death from pulmonary manifestations was proportionally increased in RA patients exposed to biologics. © 2012 Japan College of Rheumatology.

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Golimumab monotherapy in Japanese patients with active rheumatoid arthritis despite prior treatment with disease-modifying antirheumatic drugs: Results of the phase 2/3, multicentre, randomised, double-blind, placebo-controlled GO-MONO study through 24 weeks

竹内 勤

Annals of the Rheumatic Diseases （Annals of the Rheumatic Diseases）  72 （ 9 ） 1488 - 1495 2013年09月

研究論文（学術雑誌）, 査読有り,  ISSN  0003-4967

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Objective: To evaluate the efficacy and safety of golimumab 50 and 100 mg monotherapy in Japanese patients with active rheumatoid arthritis (RA) despite treatment with disease-modifying antirheumatic drugs (DMARDs). Methods: A total of 316 patients were randomised to receive subcutaneous injections every 4 weeks of placebo (group 1), golimumab 50 mg (group 2) or golimumab 100 mg (group 3); group 1 crossed over to golimumab 50 mg at week 16. The primary end point was the proportion of patients achieving ≥20% improvement in the American College of Rheumatology criteria (ACR20) at week 14. ACR50 and ACR70 response rates were also measured. Adverse events (AEs) were monitored throughout the study. Results: Demographics were similar across groups; the mean age was 52 years and 81.8% of patients (252/308) were female. Week 14 ACR20 response rates were significantly greater in groups 2 (51/101 (50.5%)) and 3 (60/102 (58.8%)) than in group 1 (20/105 (19.0%); p<0.0001 for both), as were ACR50 and ACR70 response rates. After placebo crossover at week 16, week 24 ACR response rates were similar in groups 1 and 2. Through week 16, 63.8% of patients in group 1, 62.4% in group 2 and 60.8% in group 3 had AEs and 1.9%, 1.0% and 2.0% had serious AEs. After week 16, one malignancy was reported (breast cancer, group 3). Infections were the most common AEs. No deaths or cases of tuberculosis were reported through week 24. Conclusions: Golimumab monotherapy (50 and 100 mg) was effective in reducing the signs and symptoms of RA in Japanese patients with active disease despite DMARD treatment.

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CD247 variants and single-nucleotide polymorphisms observed in systemic lupus erythematosus patients

Takeuchi T., Suzuki K.

Rheumatology (United Kingdom) （Rheumatology (United Kingdom)）  52 （ 9 ） 1551 - 1555 2013年09月

研究論文（学術雑誌）, 査読有り,  ISSN  14620324

　概要を見る

SLE is associated with a deficiency in cluster of differentiation 247 (CD247, also known as CD3 zeta chain), a component of the T-cell receptor (TCR)-CD3 complex. A comprehensive analysis showed that in more than half of SLE patients tested CD247 expression was either attenuated or absent. Recent evidence suggests that these variations in expression profiles may be due, at least in part, to polymorphisms in the CD247 gene. Aberrant CD247 transcript variants displaying either spliced exon 7 or short 3'-untranslated region have been detected in SLE T cells, and a recent genome-wide association study reported the existence of new CD247 single-nucleotide polymorphisms in SLE patients. Here, we review these unique and significant features of defective CD247 observed in SLE. © The Author 2013. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.

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American college of Rheumatology/European League Against Rheumatism remission criteria for rheumatoid arthritis maintain reliable performance when evaluated in 44 joints

Kaneko Y., Kondo H., Takeuchi T.

Journal of Rheumatology （Journal of Rheumatology）  40 （ 8 ） 1254 - 1258 2013年08月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0315-162X

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Objective. To investigate the performance of the new remission criteria for rheumatoid arthritis (RA) in daily clinical practice and the effect of possible misclassification of remission when 44 joints are assessed. Methods. Disease activity and remission rate were calculated according to the Disease Activity Score (DAS28), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), and a Boolean-based definition for 1402 patients with RA in Keio University Hospital. Characteristics of patients in remission were investigated, and the number of misclassified patients was determined - those classified as being in remission based on 28-joint count but as nonremission based on a 44-joint count for each definition criterion. Results. Of all patients analyzed, 46.6%, 45.9%, 41.0%, and 31.5% were classified as in remission in the DAS28, SDAI, CDAI, and Boolean definitions, respectively. Patients classified into remission based only on the DAS28 showed relatively low erythrocyte sedimentation rates but greater swollen joint counts than those classified into remission based on the other definitions. In patients classified into remission based only on the Boolean criteria, the mean physician global assessment was greater than the mean patient global assessment. Although 119 patients had ≤ 1 involved joint in the 28-joint count but > 1 in the 44-joint count, only 34 of these 119 (2.4% of all subjects) were found to have been misclassified into remission. Conclusion. In practice, about half of patients with RA can achieve clinical remission within the DAS28, SDAI, and CDAI; and one-third according to the Boolean-based definition. Patients classified in remission based on a 28-joint count may have pain and swelling in the feet, but misclassification of remission was relatively rare and was seen in only 2.4% of patients under a Boolean definition. The 28-joint count can be sufficient for assessing clinical remission based on the new remission criteria. Copyright © The Journal of Rheumatology 2013.

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Tolerability and efficacy of abatacept in Japanese patients with rheumatoid arthritis: A phase i study

Matsubara T., Yamana S., Tohma S., Takeuchi T., Kondo H., Kohsaka H., Ozaki S., Hashimoto H., Miyasaka N., Yamamoto A., Hiraoka M., Abe T.

Modern Rheumatology （Modern Rheumatology）  23 （ 4 ） 634 - 645 2013年07月

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

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Objective: The primary objective of this study was to evaluate the tolerability of single and multiple doses of abatacept in Japanese patients with rheumatoid arthritis. Secondary objectives included evaluating its pharmacokinetics, pharmacodynamics, immunogenicity, and efficacy. Methods: This dose-escalation, single- and multiple-dose, multicenter, open-label study was conducted at nine sites in Japan. Seven patients were enrolled at each of three dose levels (2, 8 and 16 mg/kg) and received a single intravenous dose of abatacept on day 1 of the single-dose phase. The multiple-dose phase, at the same dose, started once the patients had completed the single-dose phase and when it was confirmed that there were no safety issues. Results: Twenty patients started the single-dose phase. Single and multiple doses of abatacept were well tolerated, and adverse events were of mild to moderate intensity. There were no discontinuations or deaths due to adverse events. The pharmacokinetics of abatacept were linear, with no notable accumulation. There were no immunogenic effects on the safety, efficacy, or pharmacokinetics of abatacept. Multiple doses of abatacept improved individual items of the American College of Rheumatology core set. Conclusion: Single and multiple doses of abatacept showed favorable tolerability and efficacy in Japanese patients with rheumatoid arthritis. © 2012 Japan College of Rheumatology.

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A phase 3 randomized, double-blind, multicenter comparative study evaluating the effect of etanercept versus methotrexate on radiographic outcomes, disease activity, and safety in Japanese subjects with active rheumatoid arthritis

Takeuchi T., Miyasaka N., Zang C., Alvarez D., Fletcher T., Wajdula J., Yuasa H., Vlahos B.

Modern Rheumatology （Modern Rheumatology）  23 （ 4 ） 623 - 633 2013年07月

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

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Objectives: The aim of this phase 3, double-blind study was to compare the radiographic and clinical effects of etanercept (ETN) versus methotrexate (MTX) over 52 weeks in Japanese subjects with active rheumatoid arthritis. Methods: The study population comprised 550 subjects with inadequate response to ≥1 disease-modifying anti-rheumatic drugs who were randomized to treatment groups of ETN 25 mg twice weekly (BIW; n = 182), ETN 10 mg BIW (n = 192), or MTX (≤8.0 mg/week; n = 176). Results: Of the 550 subjects initially enrolled in the three treatment groups, 21.6 % discontinued the study; a significantly higher proportion of those who withdrew from the study due to lack of efficacy were in the MTX (21.6 %) group compared with the ETN 25 mg (3.3 %) and ETN 10 mg (6.8 %) groups (P < 0.001). Mean change from baseline in the modified total Sharp score at week 52 (primary endpoint) was significantly lower in the ETN 25 mg [3.33; standard error (SE), 0.73] and ETN 10 mg (5.19; SE 0.93) groups than in the MTX group (9.82; SE 1.16; P < 0.0001 vs. either ETN group). Compared with subjects receiving MTX, significantly higher percentages of subjects treated with ETN 25 and 10 mg achieved American College of Rheumatology (ACR) ACR20 and ACR50 response rates at all time points (P < 0.01). ETN was well-tolerated, with no unexpected safety findings. Conclusions: ETN 25 mg BIW and ETN 10 mg BIW slowed radiographic progression and improved clinical outcomes more effectively than MTX in this Japanese population. © 2012 Japan College of Rheumatology.

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[Anti-cytokine treatment, newly developed].

Hanaoka H., Takeuchi T.

Nihon rinsho. Japanese journal of clinical medicine （Nihon rinsho. Japanese journal of clinical medicine）  71 （ 7 ） 1253 - 1260 2013年07月

研究論文（学術雑誌）, 査読有り,  ISSN  00471852

　概要を見る

Rheumatoid arthritis (RA) is characterized by chronic inflammatory synovitis that causes pain, loss of function and disability, and can significantly reduce health-related quality of life. Improved understanding of the pathogenesis has led to the development of new biologic treatments that target specific cytokines. Large randomized controlled trials (RCTs) have been conducted to show the efficacy of anti-TNF and IL-6. However, despite these treatments, some patients fail to respond to these therapies. Recently other anti-ctyokine treatments had been developed and introduced. Here, we discuss about new anti-cytokine treatments for RA.

[Pharmacological management of rheumatoid arthritis: the state of the art and the future perspective].

Kameda H., Takeuchi T.

Nihon rinsho. Japanese journal of clinical medicine （Nihon rinsho. Japanese journal of clinical medicine）  71 （ 7 ） 1166 - 1171 2013年07月

研究論文（学術雑誌）, 査読有り,  ISSN  00471852

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Pharmacological management of rheumatoid arthritis (RA) has been rapidly progressed in recent years, which is appeared in the "treat to target" movement and the recommendations developed by some established international/domestic rheumatology associations. The baseline evaluation of poor prognostic factors as well as disease activity with composite measures is necessary for a personalized management. Methotrexate is currently the anchor drug, and other conventional or biological antirheumatic drugs should be added to it for refractory patients. The development of various novel agents including signal transduction inhibitors should promote further advances in the management of RA and other systemic autoimmune and/or inflammatory diseases.

TREATMENT WITH TOCILIZUMAB IMPROVED RHEUMATOID ARTHRITIS PATIENTS CLINICALLY AND STRUCTURALLY REGARDLESS OF THE PRIOR USE OF ANTI-TNF BIOLOGICS IN DAILY CLINICAL PRACTICE

竹内 勤

Annals of the Rheumatic Diseases 72   884 - 885 2013年06月

研究論文（学術雑誌）,  ISSN  0003-4967

Erratum to: Phase II dose–response study of abatacept in Japanese patients with active rheumatoid arthritis with an inadequate response to methotrexate

Takeuchi T., Matsubara T., Nitobe T., Suematsu E., Ohta S., Honjo S., Abe T., Yamamoto A., Miyasaka N.

Modern Rheumatology （Modern Rheumatology）  23 （ 2 ）  2013年03月

研究論文（学術雑誌）, 査読有り,  ISSN  14397595

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Phase II dose-response study of abatacept in Japanese patients with active rheumatoid arthritis with an inadequate response to methotrexate

Takeuchi T., Matsubara T., Nitobe T., Suematsu E., Ohta S., Honjo S., Abe T., Yamamoto A., Miyasaka N.

Modern Rheumatology （Modern Rheumatology）  23 （ 2 ） 226 - 235 2013年03月

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

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Objective: The objective of this study was to assess the response to abatacept at doses of 2 mg/kg and 10 mg/kg compared to placebo in patients with active rheumatoid arthritis (RA) with an inadequate clinical response to methotrexate (MTX). Methods: In this multicenter, placebo-controlled, doubleblind, parallel-group, dose-response study, 195 Japanese patients with active RA with an inadequate response to MTX were randomized 1:1:1 to receive 10 mg/kg or 2 mg/ kg abatacept plus MTX, or placebo plus MTX, for 24 weeks. Results: Abatacept demonstrated a dose-response relationship when given at 2 and 10 mg/kg. Based on the American College of Rheumatology criteria (20, 50, and 70 %), the responses to 10 mg/kg abatacept were significantly greater than those to placebo at week 24 (p<0.001). Smaller yet statistically significant responses were also seen in the 2 mg/kg abatacept group. Overall rates of adverse events, serious adverse events, and treatment discontinuations because of adverse events were comparable in all three groups. Conclusions: Abatacept (2 mg/kg and 10 mg/kg) showed a dose-response relationship in Japanese patients with active RA with an inadequate clinical response to MTX. Administration of abatacept in combination with MTX for 24 weeks was well tolerated. © Japan College of Rheumatology 2012.

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