研究者詳細 - 竹内　勤

論文 - 竹内　勤

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Long-term efficacy and safety of certolizumab pegol in Japanese rheumatoid arthritis patients with an inadequate response to methotrexate: 52-week results from an open-label extension of the J-RAPID study

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

Modern Rheumatology （Modern Rheumatology） 24 （ 5 ） 734 - 743 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objectives. To evaluate the long-term efficacy and safety of certolizumab pegol (CZP) plus methotrexate treatment and to assess the efficacy of two CZP maintenance dosing schedules in Japanese rheumatoid arthritis (RA) patients with an inadequate response to methotrexate. Methods. J-RAPID double-blind patients were entered into an open-label extension (OLE) study. Patients withdrawn due to lack of efficacy at 16 weeks and double-blind completers without a week-24 American College of Rheumatology (ACR) 20 response received CZP 200 mg every other week (Q2W) plus methotrexate. Double-blind completers with week-24 ACR20 responses were randomized to CZP 200 mg Q2W plus methotrexate or CZP 400 mg every 4 weeks plus methotrexate. Results. The ACR20/ACR50/ACR70 response rates of double-blind completers (n = 204) were 89.7%/67.2%/36.3% at OLE entry and 95.6%/84.8%/58.3% at 52 weeks, respectively. Other clinical, functional and radiographic outcomes were sustained with long-term CZP plus methotrexate. Long-term treatment with CZP was well-tolerated with no new unexpected adverse events observed. The efficacy and safety of CZP treatment were similar between the two dosing schedules. Conclusions. Continued CZP administration with methotrexate maintained efficacy over 52 weeks and was well-tolerated for Japanese RA patients. No obvious differences in clinical efficacy and safety were observed between the two dosing schedules, giving flexibility in maintenance administration schedules. © 2014 Japan College of Rheumatology.

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Primary and secondary surveys on epidemiology of Sjögren's syndrome in Japan

Tsuboi H., Asashima H., Takai C., Hagiwara S., Hagiya C., Yokosawa M., Hirota T., Umehara H., Kawakami A., Nakamura H., Sano H., Tsubota K., Ogawa Y., Takamura E., Saito I., Inoue H., Nakamura S., Moriyama M., Takeuchi T., Tanaka Y., Hirata S., Mimori T., Yoshifuji H., Ohta A., Matsumoto I., Sumida T.

Modern Rheumatology （Modern Rheumatology） 24 （ 3 ） 464 - 470 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objective. To characterize the epidemiology of Sjögren's syndrome (SS), including prevalence, disease type, extra-glandular involvement, satisfaction of diagnostic criteria sets, and treatment used in Japan. Methods. The Research Team for Autoimmune Diseases, the Research Program for Intractable Disease by the Ministry of Health, Labor and Welfare conducted primary and secondary surveys on epidemiology of SS in 2011. The primary survey covered 4,729 out of 14,095 Japan-wide Hospital Departments to investigate the prevalence of SS. The secondary survey encompassed 214 Hospital Departments that agreed to the survey, to characterize disease type, extra-glandular involvement, satisfaction of diagnostic criteria sets, and treatments. Results. The number of patients with SS in Japan estimated by the primary survey was 68,483. The secondary survey involving data collected from 2,195 SS patients from 98 Hospital Departments showed that the mean age of patients was 60.8 ± 15.2 years, male/female ratio was 1/17.4, primary/secondary SS was about 60%/40% and glandular/extra-glandular form in primary SS was about 70%/25%. The satisfaction rate was 53.8% for the 1999 revised Japanese Ministry of Health criteria for the diagnosis of SS, 47.7% for the 2002 American-European Consensus Group classification criteria for SS and 49.6% for 2012 American College of Rheumatology classification criteria for SS. Corticosteroids were used by 752 of 2,195 patients (34%), immunosuppressants by 358 patients (16%), biologics by 68 patients (3%) and secretagogues by 695 patients (32%). Conclusion. The surveys provided valuable information on the epidemiology of SS including prevalence, disease type, extra-glandular involvement, satisfaction of diagnostic criteria sets and treatments used today in Japan. © 2014 Japan College of Rheumatology.

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Retreatment efficacy and safety of tocilizumab in patients with rheumatoid arthritis in recurrence (RESTORE) study

Nishimoto Norihiro, Amano Koichi, Hirabayashi Yasuhiko, Horiuchi Takahiko, Ishii Tomonori, Iwahashi Mitsuhiro, Iwamoto Masahiro, Kohsaka Hitoshi, Kondo Masakazu, Matsubara Tsukasa, Mimura Toshihide, Miyahara Hisaaki, Ohta Shuji, Saeki Yukihiko, Saito Kazuyoshi, Sano Hajime, Takasugi Kiyoshi, Takeuchi Tsutomu, Tohma Shigeto, Tsuru Tomomi, Ueki Yukitaka, Yamana Jiro, Hashimoto Jun, Matsutani Takaji, Murakami Miho, Takagi Nobuhiro

Modern Rheumatology 24 （ 1 ） 26 - 32 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objectives To evaluate the safety and efficacy of retreatment with tocilizumab (TCZ) in patients who had participated in the DREAM study (Drug free remission/low disease activity after cessation of tocilizumab [Actemar] monotherapy study) and had experienced loss of efficacy. Methods Patients were retreated with TCZ or other disease modifying antirheumatic drugs (DMARDs). Disease activity was measured using the 28-joint disease activity score (DAS28) for 12 weeks. Results A total of 164 eligible patients, including 161 who experienced loss of efficacy within 52 weeks of the DREAM study, resumed treatment: 157 with TCZ and 7 with DMARDs and/or infliximab. Of TCZ-treated patients, 88.5 % (139 patients) achieved DAS28 <2.6 within 12 weeks, whereas among patients treated with DMARDs and/or infliximab only 14.3 % (1 patient) achieved DAS28 <2.6. Adverse events were observed in 70 TCZ-treated patients (44.0 %), but no serious infusion reactions were observed. Conclusions Retreatment with TCZ was well-tolerated and effective in patients who had responded to the preceding TCZ monotherapy but had experienced loss of efficacy after cessation of TCZ. © 2013 Japan College of Rheumatology.

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Effect of interleukin-6 receptor inhibitor, tocilizumab, in preventing joint destruction in patients with rheumatoid arthritis showing inadequate response to TNF inhibitors

Tanaka Y., Takeuchi T., Amano K., Saito K., Hanami K., Nawata M., Fukuyo S., Kameda H., Kaneko Y., Kurasawa T., Nagasawa H., Hoshi D., Sato E., Yamanaka H.

Modern Rheumatology （Modern Rheumatology） 24 （ 3 ） 399 - 404 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objectives. To examine the effectiveness of tocilizumab (TCZ) in preventing joint destruction in patients with inadequate response to tumor necrosis factor inhibitors (TNF-IR) by assessing X-rays. Methods. RA patients were extracted from the Retrospective actemra investigation for optimal needs of RA patients (REACTION) study. Parameters and components of disease activity were evaluated during anti-TNF treatment and during TCZ treatment. X-ray images of hands and feet at the beginning of this study during anti-TNF treatment (Pre), at the start point of TCZ treatment (Baseline) and after TCZ treatment (Post) were collected for assessing joint destruction. Results. Forty-five patients from the REACTION study fulfilled the criteria of clinical TNF-IR. During anti-TNF treatment, mean DAS28-ESR rose from 5.35 to 5.87 (mean observation duration, 16 months) but improved significantly to 2.94 (P < 0.0001) at 52 weeks after switching to TCZ. Mean change in van der Heijde-modified Sharp score (TSS) during anti-TNF treatment was 3.17 in this TNF-IR population. After switching to TCZ, mean change in TSS was 1.20 (P < 0.05). Rate of radiographic non-progression improved to 66.7% during TCZ treatment from 40.0% during anti-TNF treatment. The predictive factor for no radiographic progression after switching to TCZ was a HAQ disability index (HAQ-DI) score of ≤ 1.88 at switching to TCZ. Conclusion. TCZ was a good treatment option for improving signs and symptoms and inhibiting progression of joint damage in patients with clinical and structural TNF-IR. © 2014 Japan College of Rheumatology.

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Efficacy and safety of certolizumab pegol plus methotrexate in Japanese rheumatoid arthritis patients with an inadequate response to methotrexate: the J-RAPID randomized, placebo-controlled trial

Yamamoto K., Takeuchi T., Yamanaka H., Ishiguro N., Tanaka Y., Eguchi K., Watanabe A., Origasa H., Shoji T., Sakamaki Y., Van Der Heijde D., Miyasaka N., Koike T.

Modern Rheumatology （Modern Rheumatology） 24 （ 5 ） 715 - 724 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objectives. This 24-week, multicenter, double-blind, randomized, placebo-controlled study (NCT00791999) compared efficacy and safety of certolizumab pegol (CZP) in combination with methotrexate (MTX) vs placebo plus MTX in Japanese rheumatoid arthritis (RA) patients with inadequate response to MTX. Methods. In total, 316 patients were randomized 1:1:1:1 to subcutaneous CZP 100, 200, or 400 mg (induction dose: 200 mg or 400 mg CZP at Weeks 0, 2, and 4) plus MTX or placebo plus MTX every 2 weeks. Primary endpoint was ACR20 response at Week 12. Results. ACR20 response rates were 62.5%, 76.8%, 77.6%, and 28.6% at Week 12, and 61.1%, 73.2%, 71.8%, and 24.7% at Week 24 for CZP 100, 200, and 400 mg, and placebo groups, respectively, with statistical significance between each CZP group and placebo. Change in Total Sharp Score over 24 weeks was significantly smaller in CZP 200 and 400 mg groups vs placebo. Improvements in health-related quality of life (HRQoL) were observed in all three CZP groups vs placebo. Incidence of adverse events was similar between CZP groups. Conclusions. CZP plus MTX resulted in rapid, sustained reductions in RA signs and symptoms in Japanese patients with inadequate response to MTX, with significant inhibition of radiographic progression and improved HRQoL. © 2014 The Authors.

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Drug free REmission/low disease activity after cessation of tocilizumab (Actemra) Monotherapy (DREAM) study

Modern Rheumatology 24 （ 1 ） 17 - 25 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objectives To investigate the duration of remission and low disease activity (LDA) after cessation of tocilizumab (TCZ) treatment in rheumatoid arthritis patients who showed remission or LDA as assessed by DAS28 in response to preceding TCZ monotherapy, and to explore the factors contributing to prolonged efficacy duration. Methods Disease activity was monitored for 56 weeks. The rate of continued efficacy was estimated by Kaplan-Meier curves. Results A total of 187 patients were eligible. At baseline of this study, median disease duration was 7.8 years, preceding TCZ treatment period was 4.0 years and DAS28 was 1.5. The rate of continued LDA at 52 weeks was 13.4 % according to the Kaplan-Meier estimate. 19 patients (10 %) were completely drug-free and 17 patients (9.1 %) fulfilled DAS28 remission at 52 weeks. Multivariate Cox regression analysis identified low serum IL-6 and normalisation of MMP-3 levels at cessation of TCZ as independent predictive markers for longer duration of LDA. In patients with low serum IL-6 (<12.9 pg/mL) and normal MMP-3 levels, the rate of continued LDA reached 38.0 % at 52 weeks. Conclusions TCZ monotherapy may induce biologics-free remission or LDA without concomitant use of synthetic DMARDs. Serum levels of IL-6 and MMP-3 are useful markers for identifying patients who could discontinue TCZ without acute disease flare. © 2013 Japan College of Rheumatology.

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Baseline levels of soluble interleukin-6 receptor predict clinical remission in patients with rheumatoid arthritis treated with tocilizumab

Nishina Naoshi, Kikuchi Jun, Hashizume Misato, Yoshimoto Keiko, Kameda Hideto, Takeuchi Tsutomu

Annals of the Rheumatic Diseases 73 （ 5 ） 945 - 947 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

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Drug free REmission/low disease activity after cessation of tocilizumab (Actemra) Monotherapy (DREAM) study

Modern Rheumatology 24 17 - 25 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objectives: To investigate the duration of remission and low disease activity (LDA) after cessation of tocilizumab (TCZ) treatment in rheumatoid arthritis patients who showed remission or LDA as assessed by DAS28 in response to preceding TCZ monotherapy, and to explore the factors contributing to prolonged efficacy duration. Methods: Disease activity was monitored for 56 weeks. The rate of continued efficacy was estimated by Kaplan-Meier curves. Results: A total of 187 patients were eligible. At baseline of this study, median disease duration was 7.8 years, preceding TCZ treatment period was 4.0 years and DAS28 was 1.5. The rate of continued LDA at 52 weeks was 13.4 % according to the Kaplan-Meier estimate. 19 patients (10 %) were completely drug-free and 17 patients (9.1 %) fulfilled DAS28 remission at 52 weeks. Multivariate Cox regression analysis identified low serum IL-6 and normalisation of MMP-3 levels at cessation of TCZ as independent predictive markers for longer duration of LDA. In patients with low serum IL-6 (<12.9 pg/mL) and normal MMP-3 levels, the rate of continued LDA reached 38.0 % at 52 weeks. Conclusions: TCZ monotherapy may induce biologics-free remission or LDA without concomitant use of synthetic DMARDs. Serum levels of IL-6 and MMP-3 are useful markers for identifying patients who could discontinue TCZ without acute disease flare. © 2013 Japan College of Rheumatology.

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Post-marketing surveillance of the safety and effectiveness of tacrolimus in 3,267 Japanese patients with rheumatoid arthritis

Takeuchi Tsutomu, Kawai Shinichi, Yamamoto Kazuhiko, Harigai Masayoshi, Ishida Kota, Miyasaka Nobuyuki

Modern Rheumatology 24 8 - 16 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objectives: A post-marketing surveillance (PMS) program was implemented to assess the safety and effectiveness of tacrolimus (TAC) in Japanese rheumatoid arthritis (RA) patients and to identify risk factors related to adverse drug reactions (ADRs). Methods: Patients were registered centrally and monitored for all adverse events (AEs) for 24 weeks. Effectiveness was evaluated using the Disease Activity Score 28-CRP (DAS28-CRP). Results: Data from 3,172 patients (mean age 62.2 years) were evaluated in the safety analysis. Of the safety population, 78.5 %were female and 25.9 % were in Steinbrocker's functional class 3 or 4. TAC was prescribed as monotherapy in 52.5 % and the most common concomitant disease modifying antirheumatic drug (DMARD) was methotrexate, used in 28.9 % of the patients. The incidence of AEs, serious AEs (SAEs), ADRs and serious ADRs were 41.2, 6.4, 36.0, and 4.9 %, respectively. The most frequent serious ADR category was infections and infestations. Age ≥65 years, concurrent renal dysfunction, and concurrent diabetes mellitus were identified as significant risk factors for ADR. Based on EULAR response criteria, 65.4 % of the patients showed moderate or good response. Conclusions: The results demonstrate that TAC is well tolerated by Japanese patients with active RA, including those receiving concomitant methotrexate, in the real world. © 2013 Japan College of Rheumatology.

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Retreatment efficacy and safety of tocilizumab in patients with rheumatoid arthritis in recurrence (RESTORE) study

Modern Rheumatology 24 26 - 32 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objectives: To evaluate the safety and efficacy of retreatment with tocilizumab (TCZ) in patients who had participated in the DREAM study (Drug free remission/low disease activity after cessation of tocilizumab [Actemar] monotherapy study) and had experienced loss of efficacy. Methods: Patients were retreated with TCZ or other disease modifying antirheumatic drugs (DMARDs). Disease activity was measured using the 28-joint disease activity score (DAS28) for 12 weeks. Results: A total of 164 eligible patients, including 161 who experienced loss of efficacy within 52 weeks of the DREAM study, resumed treatment: 157 with TCZ and 7 with DMARDs and/or infliximab. Of TCZ-treated patients, 88.5 % (139 patients) achieved DAS28 <2.6 within 12 weeks, whereas among patients treated with DMARDs and/or infliximab only 14.3 % (1 patient) achieved DAS28 <2.6. Adverse events were observed in 70 TCZ-treated patients (44.0 %), but no serious infusion reactions were observed. Conclusions: Retreatment with TCZ was well-tolerated and effective in patients who had responded to the preceding TCZ monotherapy but had experienced loss of efficacy after cessation of TCZ. © 2013 Japan College of Rheumatology.

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Long-term efficacy and safety of certolizumab pegol in Japanese rheumatoid arthritis patients who could not receive methotrexate: 52-week results from an open-label extension of the HIKARI study

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

Modern Rheumatology （Modern Rheumatology） 24 （ 5 ） 725 - 733 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objectives. To evaluate the long-term efficacy and safety of certolizumab pegol (CZP) treatment and to assess the efficacy of two CZP maintenance dosing schedules in Japanese rheumatoid arthritis (RA) patients who could not receive methotrexate (MTX). Methods. HIKARI double-blind (DB) patients were entered into an open-label extension (OLE) study. Patients withdrawn at 16 weeks due to lack of efficacy and DB completers without a 24-week American College of Rheumatology (ACR)20 response received CZP 200 mg every 2 weeks (Q2W). DB completers with 24-week ACR20 responses were randomized to CZP 200 mg Q2W or CZP 400 mg every 4 weeks. Results. The ACR20/ACR50/ACR70 response rates of DB completers (n = 98) were 82.7%/56.1%/34.7% at OLE entry, and 83.7%/65.3%/48.0% at 52 weeks, respectively. Other clinical, functional, and radiographic outcomes were sustained during long-term administration of CZP, even without MTX. No new unexpected adverse events were observed during long-term CZP treatment. The efficacy and safety of CZP treatment were similar between the two dosing schedules. Conclusions. Long-term CZP administration is efficacious and safe for RA patients. No obvious differences in clinical efficacy and safety were observed between the two dosing schedules. The choice between two maintenace regimens adds flexibility in administration schedules for RA patients and physicians. © 2014 Japan College of Rheumatology.

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Discordance in global assessments between patient and estimator in patients with newly diagnosed rheumatoid arthritis: Associations with progressive joint destruction and functional impairment

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

Journal of Rheumatology （Journal of Rheumatology） 41 （ 6 ） 1061 - 1066 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

Objective. Factors relevant to the discordance between the patient global assessment (PGA) and estimator global assessment (EGA) in patients newly diagnosed with rheumatoid arthritis (RA) were examined. Methods. Seventy-five consecutive newly diagnosed patients with RA were prospectively enrolled. We used 3 models in which discordance between PGA and EGA at 12 months was set at 5 mm, 10 mm, or 20 mm. We adopted 10 mm as representative and examined time course changes in clinical variables over 12 months. Results. No significant difference was found between the concordance and the higher PGA groups regarding baseline characteristics and treatment. At 12 months, EGA, swollen joint count, and inflammatory marker values were not different, but pain visual analog scale and tender joint count were significantly higher in the higher PGA group, and the Health Assessment Questionnaire improved less. In the 10 mm and 20 mm models, the structural remission rate was significantly lower in the higher PGA group and the rapid radiological progression rate significantly higher. The discrepancy was already significant at 3 months. Conclusion. In newly diagnosed RA, PGA at 12 months may be more sensitive for indicating progressive joint destruction and functional impairment when compared with EGA, and there is a discrepancy directed toward a worse assessment by patients.

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Mice lacking inositol 1,4,5-trisphosphate receptors exhibit dry eye

Inaba T., Hisatsune C., Sasaki Y., Ogawa Y., Ebisui E., Ogawa N., Matsui M., Takeuchi T., Mikoshiba K., Tsubota K.

PLoS ONE （PLoS ONE） 9 （ 6 ） e99205 2014年

研究論文（学術雑誌）, 共著, 査読有り

Tear secretion is important as it supplies water to the ocular surface and keeps eyes moist. Both the parasympathetic and sympathetic pathways contribute to tear secretion. Although intracellular Ca2+ elevation in the acinar cells of lacrimal glands is a crucial event for tear secretion in both the pathways, the Ca2+ channel, which is responsible for the Ca 2+ elevation in the sympathetic pathway, has not been sufficiently analyzed. In this study, we examined tear secretion in mice lacking the inositol 1,4,5-trisphosphate receptor (IP3R) types 2 and 3 (Itpr2 -/-;Itpr3-/-double-knockout mice). We found that tear secretion in both the parasympathetic and sympathetic pathways was abolished in Itpr2-/-;Itpr3-/- mice. Intracellular Ca2+ elevation in lacrimal acinar cells after acetylcholine and epinephrine stimulation was abolished in Itpr2-/-;Itpr3-/- mice. Consequently, Itpr2-/-;Itpr3-/- mice exhibited keratoconjunctival alteration and corneal epithelial barrier disruption. Inflammatory cell infiltration into the lacrimal glands and elevation of serum autoantibodies, a representative marker for Sjögren's syndrome (SS) in humans, were also detected in older Itpr2-/-;Itpr3-/- mice. These results suggested that IP3Rs are essential for tear secretion in both parasympathetic and sympathetic pathways and that Itpr2 -/-;Itpr3-/- mice could be a new dry eye mouse model with symptoms that mimic those of SS. © 2014 Inaba et al.

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Safety and effectiveness of adalimumab in Japanese rheumatoid arthritis patients: Postmarketing surveillance report of 7740 patients

Koike T., Harigai M., Ishiguro N., Inokuma S., Takei S., Takeuchi T., Yamanaka H., Haruna S., Ushida N., Kawana K., Tanaka Y.

Modern Rheumatology （Modern Rheumatology） 24 （ 3 ） 390 - 398 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objectives. To confirm the safety and effectiveness of adalimumab and to evaluate the influence of the concomitant use of methotrexate (MTX). Methods. Postmarketing surveillance of 7740 Japanese rheumatoid arthritis (RA) patients was performed. All patients who received adalimumab in the registration period were followed for 28 weeks after starting treatment for safety and 24 weeks for effectiveness. Effectiveness was measured by duration of morning stiffness, swollen and tender joint counts (28 joints), patient global assessment of disease activity, erythrocyte sedimentation rate and serum C-reactive protein. Results. Comparable rates of adverse drug reactions (ADRs) were reported in this study and in the interim analysis. Age, pulmonary disease history or comorbidity, co-existing diabetes mellitus, concomitant MTX at doses of > 8 mg/week and concomitant glucocorticoids at doses of > 5 mg/day were risk factors for infections. All mean values of effectiveness measurements improved. Relatively lower disease activity at baseline, biologic-naïve, concomitant MTX use and early RA stage/low functional class were background factors contributing to the effectiveness. The combination of adalimumab with MTX improved the response to adalimumab treatment. Conclusion. Adalimumab, especially with concomitant use of MTX, provided significant improvement in disease activity, without any unexpected ADRs in Japanese RA patients. © 2014 Japan College of Rheumatology.

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A single nucleotide polymorphism of TRAF1 predicts the clinical response to anti-TNF treatment in Japanese patients with rheumatoid arthritis

Nishimoto T., Seta N., Anan R., Yamamoto T., Kaneko Y., Takeuchi T., Kuwana M.

Clinical and Experimental Rheumatology （Clinical and Experimental Rheumatology） 32 （ 2 ） 211 - 217 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0392-856X

Objective: Recent genome-wide association studies disclosed that several single nucleotide polymorphisms (SNPs), including tumour necrosis factor (TNF) receptor-associated factor 1 (TRAF1) (+16860A/G), are associated with the pathophysiology of rheumatoid arthritis (RA). We assessed the usefulness of TRAF1 genotyping as a genetic predictor of the response to anti-TNF treatment in Japanese RA patients. Methods: TRAF1 (+16860A/G) was genotyped using the TaqMan SNP genotyping assay in 101 Japanese RA patients treated with anti-TNF drugs for >24 weeks. We retrospectively analysed the association between SNP and the clinical response to treatment. TRAF1 mRNA and protein expression was also evaluated in CD4+, CD8+, CD14+, or CD19+ cells from 25 healthy subjects using quantitative polymerase chain reaction and intracellular staining flow cytometry, respectively. Results: No statistical difference in DAS28-ESR at baseline was observed between the patient groups with the AA, AG, or GG genotype. The GG genotype was more frequent in non-responders than in good or moderate responders [odds ratio (OR) 7.4, 95% confidence interval (CI) 1.5-37.5]. The non-responders possessed the G allele more frequently than the good or moderate responders (OR 3.5, 95% CI 1.4-9.0). TRAF1 protein expression increased significantly in CD14+ monocytes from healthy subjects with the GG genotype compared with that in subjects with the AA or AG genotype. Conclusion: TRAF1 (+16860A/G) may be useful for predicting the clinical response to anti-TNF treatment and may contribute to resistance to treatment in RA patients with the GG genotype by increasing the TRAF1 expression in circulating inflammatory cells. © Clinical and experimental rheumatology 2014.

Phase III, multicenter, open-label, long-term study of the safety of abatacept in Japanese patients with rheumatoid arthritis and an inadequate response to conventional or biologic disease-modifying antirheumatic drugs

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

Modern Rheumatology （Modern Rheumatology） 24 （ 5 ） 744 - 753 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objectives. To examine the long-term safety of intravenous (IV) abatacept treatment in Japanese patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX) or other conventional or biologic disease-modifying antirheumatic drugs. Methods. This Phase III, open-label, long-term study (NCT00484289) comprised Japanese patients with RA who had completed abatacept Phase I or Phase II studies, and new patients intolerant to MTX. Patients from Phase I and Phase II studies received a weight-tiered dosing equivalent of 10 mg/kg abatacept, with MTX at doses up to 8 mg/week; newly enrolled patients received weight-tiered 10 mg/kg abatacept monotherapy. Safety and efficacy were assessed. Results. A total of 217 patients (Phase I, n = 13; Phase II, n = 178; newly enrolled, n = 26) were treated with IV abatacept for a mean of 3 years. Serious adverse events occurred in 67/217 (30.9%) patients. Most adverse events were mild or moderate. For all cohorts combined, American College of Rheumatology 20% response rates ranged from 61.3 to 81.8% for as-observed and last observation carried forward analyses over 192 weeks. Following initial response, clinical and functional outcomes were maintained for up to 3 years. Conclusions. In Japanese patients with RA, IV abatacept with and without background MTX showed tolerable safety and sustained efficacy over 3 years. © 2014 Japan College of Rheumatology.

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Efficacy and safety of abatacept in routine care of patients with rheumatoid arthritis: Orencia® as Biological Intensive Treatment for RA (ORBIT) study

Tanaka Y., Kubo S., Yamanaka H., Amano K., Hirata S., Tanaka E., Nagasawa H., Yasuoka H., Takeuchi T.

Modern Rheumatology （Modern Rheumatology） 24 （ 5 ） 754 - 762 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objective. To investigate the efficacy and safety of abatacept for treating patients with rheumatoid arthritis (RA) in routine clinical practice. Methods. We performed a retrospective study of 137 RA patients who were treated with abatacept for 24 weeks between October 2010 and June 2011 at four rheumatology centers in Japan. Outcomes were compared between biologic-naïve and biologic-experienced patients. Disease activity was assessed using the Simplified Disease Activity Index (SDAI) and the 28-joint Disease Activity Score based on the erythrocyte sedimentation rate (DAS28-ESR). Results. The retention rate of abatacept at 24 weeks was 79.6%. SDAI (from 24.6 ± 12.5 to 12.9 ± 11.6) and DAS28-ESR (from 5.2 ± 1.4 to 3.9 ± 1.4) decreased significantly from baseline to Week 24 (both P < 0.001). Remission/low disease activity were achieved in 2.2%/11.2% (SDAI) and in 5.3%/2.3% (DAS28-ESR). The change in SDAI and the remission/low disease activity rates at Week 24 was greater in biologic-naïve patients than in biologic-experienced patients. Structural remission (van der Heijde-modified total Sharp score ≤ 0.5) was achieved by 63.4% of patients. Conclusions. The present results confirm that abatacept is effective in routine clinical practice and support its use as the first-line biologic agent in patients. © 2014 Japan College of Rheumatology.

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Efficacy and safety of certolizumab pegol without methotrexate co-administration in Japanese patients with active rheumatoid arthritis: The HIKARI randomized, placebo-controlled trial

Yamamoto K., Takeuchi T., Yamanaka H., Ishiguro N., Tanaka Y., Eguchi K., Watanabe A., Origasa H., Iwai K., Sakamaki Y., Van Der Heijde D., Miyasaka N., Koike T.

Modern Rheumatology （Modern Rheumatology） 24 （ 4 ） 552 - 560 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objective. This 24-week, placebo-controlled, double-blind, randomized study (NCT00791921) investigated efficacy and safety of certolizumab pegol (CZP) in Japanese rheumatoid arthritis (RA) patients in whom methotrexate (MTX) cannot be administered. Methods. A total of 230 patients were randomized to subcutaneous CZP 200 mg (induction dosing: 400 mg at Weeks 0, 2 and 4) or placebo every 2 weeks. Results. ACR20 responses with CZP were rapid and significant versus placebo at Week 1, sustained to Week 12 (67.2% vs. 14.9%) and Week 24 (63.8% vs. 11.4%). Week 24-modified Total Sharp Score (mTSS) change from baseline (CFB) was 0.48 (CZP) versus 2.45 (placebo). CZP treatment was associated with higher Week 12 ACR20 responses versus placebo (with non-MTX disease modifying antirheumatic drugs [DMARDs], 74.2% vs. 20.0%; without [monotherapy], 59.3% vs. 8.2%) and inhibition of radiographic progression at Week 24 (mTSS CFB; with non-MTX DMARDs, 0.24 vs. 1.61; monotherapy, 0.68 vs. 3.65). Incidences of serious adverse events were 11.2% (CZP) and 2.6% (placebo); one CZP patient died of dissecting aortic aneurysm. Conclusion. CZP treatment with and without non-MTX DMARDs in Japanese patients in whom MTX cannot be administered resulted in rapid, sustained reductions in RA signs and symptoms. Notably, CZP monotherapy showed significant inhibition of radiographic progression. © 2014 The Authors.

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Recovery of clinical but not radiographic outcomes by the delayed addition of adalimumab to methotrexate-treated japanese patients with early rheumatoid arthritis: 52-week results of the hopeful-1 trial

Yamanaka H., Ishiguro N., Takeuchi T., Miyasaka N., Mukai M., Matsubara T., Uchida S., Akama H., Kupper H., Arora V., Tanaka Y.

Rheumatology (United Kingdom) （Rheumatology (United Kingdom)） 53 （ 5 ） 904 - 913 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1462-0324

Objective: The aim of this study was to compare efficacy outcomes of initial treatment with adalimumab + MTX vs adalimumab addition following 26 weeks of MTX monotherapy in Japanese early RA patients naive to MTX with high disease activity. Methods: Patients completing the 26-week, randomized, placebo-controlled trial of adalimumab + MTX were eligible to receive 26 weeks of open-label adalimumab + MTX. Patients were assessed for mean change from baseline in the 28-joint DAS with ESR (DAS28-ESR) and modified total Sharp score (mTSS), and for the proportions of patients achieving clinical, functional or radiographic remission. Results: Of 333 patients assessed, 278 (137 from the initial adalimumab + MTX and 141 from the initial placebo + MTX groups) completed the 52-week study. Significant differences in clinical and functional parameters observed during the 26-week blinded period were not apparent following the addition of open-label adalimumab to MTX. Open-label adalimumab + MTX slowed radiographic progression through week 52 in both groups, but patients who received adalimumab + MTX throughout the study exhibited less radiographic progression than those who received placebo + MTX during the first 26 weeks (mean ΔmTSS at week 52 = 2.56 vs 3.30, P < 0.001). Conclusion: Delayed addition of adalimumab in Japanese MTX-naive early RA patients did not impact clinical and functional outcomes at week 52 compared with the earlier addition of adalimumab. However, the accrual of significant structural damage during blinded placebo + MTX therapy contributed to the persistence of differences between the treatment strategies, suggesting that Japanese patients at risk for aggressive disease should benefit from the early inclusion of adalimumab + MTX combination therapy.Trial registration. ClinicalTrials.gov (http://clinicaltrials.gov/), NCT00870467. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology.

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Distinct arthropathies of the hands in patients with anti-aminoacyl trna synthetase antibodies: Usefulness of autoantibody profiles in classifying patients

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

Rheumatology (United Kingdom) （Rheumatology (United Kingdom)） 53 （ 6 ） 1120 - 1124 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1462-0324

Objective: The aim of this study was to characterize arthropathies of the hands associated with anti-aminoacyl tRNA synthetase (ARS) autoantibodies. Methods: Fifty-six patients with anti-ARS antibodies were selected from consecutive patients who visited Keio University Hospital between1983 and 2011, based on their joint symptoms and the availability of hand X-rays. Their clinical characteristics, anti-CCP antibodies, RF, and hand X-ray findings were retrospectively examined. Results: Based on characteristic hand X-ray findings, the anti-ARS-positive patients with joint symptoms could largely be categorized into three groups. The predominant group (64%) was patients with no significant X-ray findings. The remaining patients with destructive changes were classified into two distinct groups. One group had mainly erosions in the PIP and MCP joints and/or ankylosis of the wrists with anti-CCP and RF, which is consistent with the features of RA. The other group showed subluxation of the thumbs and periarticular calcification that was independent of anti-CCP or RF, which is exclusively found in anti-Jo-1-positive patients. Conclusion: Autoantibody profiles, including anti-CCP, RF and individual anti-ARS specificities, are useful in classifying anti-ARS-associated arthropathies of the hands into RA or anti-Jo-1-related disorders. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.

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