研究者詳細 - 竹内　勤

論文 - 竹内　勤

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Resolution of elevated circulating regulatory T cells by corticosteroids in patients with IgG4-related dacryoadenitis and sialoadenitis

Akiyama Mitsuhiro, Suzuki Katsuya, Kassai Yoshiaki, Miyazaki Takahiro, Morita Rimpei, Yoshimura Akihiko, Takeuchi Tsutomu

International Journal of Rheumatic Diseases 190 （ 4 ） 430 - 432 2016年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1756-1841

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Comparison of the clinical effectiveness of tumour necrosis factor inhibitors and abatacept after insufficient response to tocilizumab in patients with rheumatoid arthritis

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

Clinical Rheumatology （Clinical Rheumatology） 35 （ 11 ） 2829 - 2834 2016年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0770-3198

© 2016, International League of Associations for Rheumatology (ILAR). The aim of this study is to compare the clinical effectiveness of tumour necrosis factor inhibitors (TNFi) and abatacept (ABT) after insufficient response to tocilizumab (TCZ) in patients with rheumatoid arthritis (RA). Among 527 RA patients treated with TCZ, 63 patients were enrolled who switched TCZ to alternative biologic agents because of moderate or high disease activity assessed by the Clinical Disease Activity Index (CDAI). They were divided into two groups, TNF inhibitors (TNFi) or abatacept (ABT), and compared for clinical effectiveness and adverse events at week 24. Forty-two were switched to TNFi, and 21 to ABT. TNFi included 19 infliximab, 3 adalimumab, 8 etanercept, 9 golimumab, and 3 certolizumab-pegol. Baseline characteristics at the switch were comparable except for the concomitant methotrexate use (TNFi 71.4 vs ABT 28.6 %, P = 0.003). The proportion of patients achieving CDAI ≤ 10 (remission or low disease activity) at week 24 was significantly higher in TNFi than ABT (64.3 vs 23.8 %, P = 0.003), and the values of the CDAI at week 24 was significantly better in TNFi than ABT (mean, 11.8 vs 16.4, P = 0.021) although the drug retention rate was not different between the two groups (73.8 vs 71.4 %, P = 0.803). No serious adverse event was observed in both groups. TNFi may be more effective than ABT to achieve clinical remission or low disease activity after insufficient response to TCZ in patients with RA, although drug retention rate and safety are comparable.

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Adalimumab discontinuation in patients with early rheumatoid arthritis who were initially treated with methotrexate alone or in combination with adalimumab: 1 year outcomes of the HOPEFUL-2 study

Tanaka Y., Yamanaka H., Ishiguro N., Miyasaka N., Kawana K., Hiramatsu K., Takeuchi T.

RMD Open （RMD Open） 2 （ 1 ） e000189 2016年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2056-5933

Objectives: To evaluate the impact of discontinuation of adalimumab (ADA) for 1 year in Japanese patients with early rheumatoid arthritis (RA). Methods: This 52-week postmarketing study, HOPEFUL-2, enrolled patients who had completed HOPEFUL-1 for early RA, in which patients received either ADA + methotrexate (MTX) or MTX alone in a 26-week randomised phase, followed by ADA+MTX in a 26-week open-label phase. Results: A total of 220 patients (ADA discontinuation: 114 patients vs ADA continuation: 106 patients) were enrolled in this study. The proportion of patients with sustained low disease activity (LDA) in the ADA discontinuation group was significantly lower than that in the continuation group (80% (64/80 patients) vs 97% (71/73 patients); p=0.001); however, most patients sustained LDA in both groups. In patients with 28-joint disease activity score (DAS28)-C reactive protein ≤2.0 at week 52, the proportion of patients who achieved sustained LDA at week 104 was 93%, suggesting that DAS28 remission may be a predictor to indicate biologicalfree disease control in patients with early RA. The incidence of adverse events (AE) was significantly lower in the ADA discontinuation group than in the continuation group (34.2% (39/114 patients) vs 48.1% (51/106 patients); p=0.04), most notably for infection (14.9% vs 27.4%, p=0.031). Conclusions: Although ADA discontinuation was associated with an increase in disease activity, a large proportion of patients maintained LDA with MTX monotherapy after ADA discontinuation. Since ADA discontinuation was associated with a lower AE incidence, physicians should weigh the risks and benefits of ADA discontinuation.

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Prevention of joint destruction in patients with high disease activity or high C-reactive protein levels: Post hoc analysis of the GO-FORTH study

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

Modern Rheumatology （Modern Rheumatology） 26 （ 3 ） 323 - 330 2016年03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 assess the influence of golimumab dosage and disease activity on joint destruction in patients with active rheumatoid arthritis (RA) in the GO-FORTH study.Methods: Efficacy was compared among groups given basal methotrexate plus placebo, golimumab (50 mg), or golimumab (100 mg) with stratification by high (HDA) or moderate (MDA) baseline disease activity and by high or low baseline C-reactive protein (CRP).Results: Among HDA or high CRP patients, the mean change of the total Sharp score was 3.48 and 3.41 in the placebo group, 1.94 and 2.71 in the 50 mg group, and 0.39 and 1.15 in the 100 mg group, respectively. The percentage of progression-free patients with HDA or high CRP was 40.4% and 40.0%, 43.1% and 38.2%, and 69.8% and 61.5%, respectively. Among MDA or low CRP patients, both golimumab doses showed similar prevention of joint destruction. Among HDA or high CRP patients, a shorter disease duration and higher TSS/disease duration ratio were associated with joint destruction.Conclusion: Both doses of golimumab (50 or 100 mg) prevented joint destruction in MDA or low CRP patients, but 100 mg was better for HDA or high CRP patients with a shorter disease duration or higher TSS/disease duration ratio.

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Intriguing findings of the muscle on magnetic resonance imaging in polyarteritis nodosa

Takei H., Hanaoka H., Kaneko Y., Yamaoka K., Sasaki A., Takeuchi T.

Internal Medicine （Internal Medicine） 55 （ 21 ） 3197 - 3200 2016年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0918-2918

© 2016 The Japanese Society of Internal Medicine. Polyarteritis nodosa (PAN) confined to the muscle is rare and hard to diagnose. Recently, the utility of magnetic resonance imaging (MRI) for detecting muscle involvement of PAN has been introduced. We herein report the case of biopsy-proven, refractory PAN confined to the lower limb muscles with enhanced MRI demonstrating discretely granular hyperintensities, which was contrary to previous reports. Our results, with those of previous reports, suggest that the MRI findings of muscles in PAN reflect the vessel size involved and disease severity.

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Serum proteomic analysis identifies interleukin 16 as a biomarker for clinical response during early treatment of rheumatoid arthritis

Murota A., Suzuki K., Kassai Y., Miyazaki T., Morita R., Kondo Y., Takeshita M., Niki Y., Yoshimura A., Takeuchi T.

Cytokine （Cytokine） 78 87 - 93 2016年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1043-4666

© 2015 Elsevier Ltd. Objectives: To conduct a comprehensive quantitative proteomics analysis of novel serum protein biomarkers based on synovitis status associated with matrix metalloproteinase-3 (MMP-3) and to determine the clinical significance of these biomarkers in rheumatoid arthritis (RA). Methods: Patients with untreated RA (n=28), primary Sjogren's syndrome (pSS) (n=30), and healthy controls (HCs) (n=30) were enrolled for the screening assay. A total of 1128 serum proteins were analyzed using the SOMAscan™ assay. Serum levels of MMP-3 and interleukin (IL)-16 were measured using a latex turbidimetric immunoassay and ELISA at baseline and 12 weeks after treatment with methotrexate (MTX) for MTX-naïve RA patients (n=28) or with the biologics tocilizumab (TCZ) (n= 7), abatacept (ABT) (n=11) or infliximab (n=22) for MTX-inadequate response (IR) RA patients. Correlation analysis was conducted using Spearman's rank correlation method. Results: Proteomics showed that serum IL-16 levels were most positively correlated with those of MMP-3 (ρ= 0.51, p< 0.01) and were significantly increased in patients with untreated active RA compared to HCs (p< 0.01) or those with pSS (p< 0.01). IL-16 levels decreased following treatment in both the MTX-naïve and MTX-IR groups. Regarding clinical response, fluctuations in IL-16 levels were positively associated with changes in clinical indicators, particularly the Clinical Disease Activity Index (ρ= 0.89, p< 0.01) in the TCZ and ABT-treated group. However, no similar correlation was noted in MMP-3 and acute phase reactants in any groups. Conclusions: IL-16 was a more effective clinical parameter than MMP-3, C-reactive protein, or erythrocyte sedimentation rate in both MTX-naive and MTX-IR RA patients. IL-16 might be a useful biomarker for evaluating clinical response in RA patients.

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Tofacitinib, an oral Janus kinase inhibitor, as monotherapy or with background methotrexate, in Japanese patients with rheumatoid arthritis: An open-label, long-term extension study

Yamanaka H., Tanaka Y., Takeuchi T., Sugiyama N., Yuasa H., Toyoizumi S., Morishima Y., Hirose T., Zwillich S.

Arthritis Research and Therapy （Arthritis Research and Therapy） 18 （ 1 ） 34 2016年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1478-6354

© 2016 Yamanaka et al. Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. Here, tofacitinib safety and efficacy data from a long-term extension study in Japanese patients are presented. Methods: Study A3921041 was a multi-centre, open-label, long-term extension study that included Japanese patients who had participated in a prior Phase 2 or Phase 3 study of tofacitinib as monotherapy or with background methotrexate. Patients received tofacitinib 5 mg twice daily (BID) or tofacitinib 10 mg BID. Dose adjustment of tofacitinib during treatment period, and concomitant usage of disease-modifying antirheumatic drugs including methotrexate after week 12 were permitted. Primary endpoints were adverse events, laboratory parameters and vital signs. Secondary efficacy endpoints included American College of Rheumatology (ACR)20/50/70 response rates, Disease Activity Score (DAS)28-4(erythrocyte sedimentation rate (ESR))<2.6 response rate (DAS-defined remission) and Health Assessment Questionnaire-Disability Index (HAQ-DI) score. Safety and efficacy data were assessed throughout the study. Results: A total of 486 patients were recruited and treated (1439.9 patient-years of exposure). 308 patients completed the study. Median (range) duration of treatment in this extension study was 1185 (5-2016) days. 476 patients (97.9 %) experienced adverse events; the majority of which (97.8 %) were of mild or moderate severity. The two most common treatment-emergent adverse events were nasopharyngitis (n = 293, 60.3 %) and herpes zoster (n = 94, 19.3 %). For all tofacitinib-treated patients, the incidence rate (patients with events per 100 patient-years) was 10.7 for serious adverse events, 3.3 for serious infections, 7.4 for herpes zoster (serious and non-serious) and 1.2 for malignancies (excluding non-melanoma skin cancer). Mean changes from baseline (start of the index study) in laboratory parameters were consistent with those seen in previously reported studies of tofacitinib. ACR20/50/70 response rates, DAS-defined remission rates and HAQ-DI scores were sustained through to study completion. Conclusions: Tofacitinib (with or without background methotrexate) demonstrated a stable safety profile and sustained efficacy in Japanese patients with active rheumatoid arthritis. The risk of herpes zoster appears to be higher in Japanese patients treated with tofacitinib than in the global population. Trial registration: Clinicaltrials.gov NCT00661661. Registered 7 February 2008.

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Poor renal outcomes in patients with anti-neutrophil cytoplasmic antibody-associated crescentic glomerulonephritis and normal renal function at diagnosis

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

Clinical Rheumatology （Clinical Rheumatology） 35 （ 2 ） 495 - 500 2016年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0770-3198

© 2016, International League of Associations for Rheumatology (ILAR). The aim of this study is to investigate the renal outcomes of anti-neutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis in patients with normal estimated glomerular filtration rate (eGFR) at diagnosis. Twenty-seven patients with biopsy-proven ANCA-associated crescentic glomerulonephritis were retrospectively recruited and were divided into 12 with normal eGFR (≥60 ml/min/1.73 m2) and 15 with low eGFR (<60 ml/min/1.73 m2) at baseline. Clinical and renal pathological findings at diagnosis and renal outcomes for up to 3 years were compared between the two groups. Two patients in the low eGFR group died of severe bacterial pneumonia. In the normal eGFR group, the following characteristics were observed: younger age at diagnosis (p = 0.04), diagnosis of granulomatosis polyangiitis (GPA) (p < 0.01), and lower frequency of cyclophosphamide treatment (p = 0.03). On renal pathological analysis, the normal eGFR group had a significantly lower proportion of cellular crescent formation (p = 0.01), fibrinoid necrosis (p = 0.01), interstitial fibrosis (p = 0.02), and tubular atrophy (p = 0.02). As a result, the two groups did not significantly differ in remission rates, relapse rates, Birmingham vasculitis score, vasculitis damage index, or eGFR on 3-year follow-up. Patients with biopsy-proven ANCA-associated glomerulonephritis and normal eGFR at diagnosis have poor renal outcomes and may require standard intensive immunosuppressive treatment to prevent accrual of damage.

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Postmarketing surveillance of the safety and effectiveness of abatacept in Japanese patients with rheumatoid arthritis

Harigai M., Ishiguro N., Inokuma S., Mimori T., Ryu J., Takei S., Takeuchi T., Tanaka Y., Takasaki Y., Yamanaka H., Watanabe M., Tamada H., Koike T.

Modern Rheumatology （Modern Rheumatology） 26 （ 4 ） 491 - 498 2016年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2016 Japan College of Rheumatology. Objective: To perform a postmarketing surveillance study evaluating the safety and effectiveness of abatacept in Japanese patients with rheumatoid arthritis (RA). Methods: Safety and effectiveness data were collected for all RA patients (at 772 sites) treated with intravenous abatacept between September 2010 and June 2011. Patients were treated by the approved dosing regimen according to the package insert. Treatment effectiveness was evaluated at baseline and at weeks 4, 12, and 24 using Disease Activity Score 28 (DAS28) according to erythrocyte sedimentation rate or serum C-reactive protein concentrations. Results: Overall, 3882 and 3016 abatacept-naïve RA patients were included in safety and effectiveness analyses, respectively. Adverse drug reactions (ADRs) were reported for 15.66% of patients and serious ADRs were detected for 2.52% of patients. The incidence of serious infections was 1.03% and these were mainly attributed to different types of bacterial pneumonia. Disease activity improved significantly over 6 months. Separate multivariate analysis identified predictors of severe ADR, and severe infections and factors predictive of clinically meaningful DAS28 improvement after 6 months of treatment with abatacept. Conclusions: Abatacept was efficacious and well tolerated in a clinical setting. No new safety concerns were detected.

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Comparison of adding tocilizumab to methotrexate with switching to tocilizumab in patients with rheumatoid arthritis with inadequate response to methotrexate: 52-week results from a prospective, randomised, controlled study (SURPRISE study)

Kaneko Y., Atsumi T., Tanaka Y., Inoo M., Kobayashi-Haraoka H., Amano K., Miyata M., Murakawa Y., Yasuoka H., Hirata S., Nagasawa H., Tanaka E., Miyasaka N., Yamanaka H., Yamamoto K., Takeuchi T.

Annals of the Rheumatic Diseases （Annals of the Rheumatic Diseases） 75 （ 11 ） 1917 - 1923 2016年01月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

© 2016 Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to. Objective To compare the efficacy and safety between tocilizumab added to methotrexate and tocilizumab switched from methotrexate in patients with active rheumatoid arthritis (RA). Methods This is a 2-year randomised, controlled study. RA patients with moderate or high disease activity despite methotrexate were randomly assigned either to tocilizumab added to methotrexate (add-on) or tocilizumab switched from methotrexate (switch). The primary endpoint was the DAS28 remission rate at week 24. Secondary objectives included other clinical efficacy indices, radiological outcomes assessed with the van der Heijde-modified total Sharp scoring system (mTSS), and safety. Results Of 223 randomised patients, 83% completed 52â €..weeks. DAS28 remission rates at week 24 were 70% for add-on and 55% for switch (p=0.02), but they became comparable at week 52 (72% vs 70%, p=0.86). Structural remission rates (mTSS≤0.5) at week 52 were not different (66% vs 64%, p=0.92). However, clinically relevant radiographic progression rates (CRRP; mTSS≥3) tended to be higher with the switch than with the add-on (15% vs 7%, p=0.07). Radiographic progression in the CRRP patients was larger with the switch than with the add-on (9.0/year vs 5.0/year, p=0.04). The difference in the mean C-reactive protein of the CRRP patients was significant for the first 24â €..weeks (1.56 vs 0.49, p=0.001) but not for the following 28â €..weeks (0.10 vs 0.04, p=0.1). Overall safety was preferable in the switch group. Conclusions In RA patients with inadequate response to methotrexate, tocilizumab added to methotrexate more rapidly suppressed inflammation than tocilizumab switched from methotrexate, leading to superior clinical efficacy and prevention of joint destruction. Trial registration number NCT01120366.

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Efficacy and safety of rituximab in Japanese patients with systemic lupus erythematosus and lupus nephritis who are refractory to conventional therapy

Tanaka Y., Takeuchi T., Miyasaka N., Sumida T., Mimori T., Koike T., Endo K., Mashino N., Yamamoto K.

Modern Rheumatology （Modern Rheumatology） 26 （ 1 ） 80 - 86 2016年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2015 Japan College of Rheumatology. Published by Taylor & Francis. Objectives. To evaluate the efficacy and safety of rituximab in Japanese patients with systemic lupus erythematosus (SLE) and lupus nephritis (LN) who are refractory to conventional immunosuppressive therapy.Methods. Eligible patients received rituximab at a dose of 1,000 mg at days 1, 15, 169, and 183, and were followed for 53 weeks after the first dose of rituximab. Overall disease activity was assessed monthly using a British Isles Lupus Assessment Group activity index. Patients with LN (Upr/Ucr ≥ 1.0 at study entry) were identified and their renal responses were evaluated according to the criteria proposed by the American College of Rheumatology (ACR) and the Lupus Nephritis Assessment with Rituximab (LUNAR) study.Results. A total of 34 patients were enrolled and received at least one dose of rituximab. Decrease in disease activity was achieved in 16 (76.5%) out of 34 patients. In 17 patients with LN, response rates of 58.8% and 52.9% by ACR and LUNAR criteria, respectively, were seen. Successful steroid tapering was achieved in association with disease remission. Rituximab was well tolerated, and most adverse drug reactions were grade 1-2 in severity.Conclusions. Rituximab is effective for treatment of Japanese patients with SLE and LN refractory to conventional therapy.

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Efficacy and safety of olokizumab in Asian patients with moderate-to-severe rheumatoid arthritis, previously exposed to anti-TNF therapy: Results from a randomized phase II trial

Takeuchi T., Tanaka Y., Yamanaka H., Amano K., Nagamine R., Park W., Shiozawa K., Tsukano M., Wei J., Shao J., Togo O., Mashimo H.

Modern Rheumatology （Modern Rheumatology） 26 （ 1 ） 15 - 23 2016年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2015 Japan College of Rheumatology. Published by Taylor & Francis. Objectives: This phase II, dose-ranging, double-blind, placebo-controlled, randomized study (NCT01463059) evaluated efficacy and safety of olokizumab (OKZ), a humanized anti-interleukin 6 monoclonal antibody, in Asian patients with moderately-to-severely active rheumatoid arthritis (RA) who had previously failed anti-TNF therapy.Methods: Patients were randomized to one of six treatment arms: placebo or OKZ (60 mg/120 mg/240 mg every four weeks [Q4W]; or 60 mg/120 mg every two weeks [Q2W]); stratified by country and number of prior anti-TNFs. Primary efficacy variable was Week 12 change from baseline (CFB) in DAS28 CRP for 4-week cumulative dose groups of OKZ and placebo; secondary efficacy variables were Week 12 ACR20/ACR50/ACR70 response rates. Patients continued MTX treatment from baseline, without additional csDMARDs.Results: Of 119 randomized patients, 88.2% completed the study. Greater improvements in DAS28(CRP) mean CFB at Week 12 were observed in all OKZ 4-week cumulative dose groups (60 mg/120 mg/240 mg) versus placebo (p < 0.0001). Week 12 ACR20/ACR50 response rates were higher in all OKZ cumulative dose groups versus PBO (p < 0.05). Incidences of adverse events were similar across OKZ 4-week cumulative dose groups (76.9-84.4%) and placebo (82.8%) with no deaths.Conclusions: OKZ demonstrated improvements in efficacy variables versus placebo in Asian patients with moderately-to-severely active RA who had previously failed anti-TNF therapy. The safety profile was as expected for this class of drug.

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The first double-blind, randomised, parallel-group certolizumab pegol study in methotrexate-naïve early rheumatoid arthritis patients with poor prognostic factors, C-OPERA, shows inhibition of radiographic progression

Atsumi T., Yamamoto K., Takeuchi T., Yamanaka H., Ishiguro N., Tanaka Y., Eguchi K., Watanabe A., Origasa H., Yasuda S., Yamanishi Y., Kita Y., Matsubara T., Iwamoto M., Shoji T., Okada T., Van Der Heijde D., Miyasaka N., Koike T.

Annals of the Rheumatic Diseases （Annals of the Rheumatic Diseases） 75 （ 1 ） 75 - 83 2016年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

Objectives To evaluate efficacy and safety of combination therapy using certolizumab pegol (CZP) and methotrexate (MTX) as first-line treatment for MTXnaive, early rheumatoid arthritis (RA) with poor prognostic factors, compared with MTX alone. Methods MTX-naive, early RA patients with ≤12 months persistent disease, high anti-cyclic citrullinated peptide, and either rheumatoid factor positive and/or presence of bone erosions were enrolled in this multicentre, double-blind, randomised placebo (PBO)-controlled study. Patients were randomised 1:1 to CZP+MTX or PBO+MTX for 52 weeks. Primary endpoint was inhibition of radiographic progression (change from baseline in modified Total Sharp Score (mTSS CFB)) at week 52. Secondary endpoints were mTSS CFB at week 24, and clinical remission rates at weeks 24 and 52. Results 316 patients randomised to CZP+MTX (n=159) or PBO+MTX (n=157) had comparable baseline characteristics reflecting features of early RA (mean disease duration: 4.0 vs 4.3 months; Disease Activity Score 28-joint assessment (DAS28)) (erythrocyte sedimentation rate (ESR)): 5.4 vs 5.5; mTSS: 5.2 vs 6.0). CZP+MTX group showed significantly greater inhibition of radiographic progression relative to PBO+MTX at week 52 (mTSS CFB=0.36 vs 1.58; p<0.001) and week 24 (mTSS CFB=0.26 vs 0.86; p=0.003). Clinical remission rates (Simple Disease Activity Index, Boolean and DAS28 (ESR)) of the CZP+MTX group were significantly higher compared with those of the PBO +MTX group, at weeks 24 and 52. Safety results in both groups were similar, with no new safety signals observed with addition of CZP to MTX. Conclusions In MTX-naive early RA patients with poor prognostic factors, CZP+MTX significantly inhibited structural damage and reduced RA signs and symptoms, demonstrating the efficacy of CZP in these patients.

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Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force

Smolen J., Breedveld F., Burmester G., Bykerk V., Dougados M., Emery P., Kvien T., Navarro-Compán M., Oliver S., Schoels M., Scholte-Voshaar M., Stamm T., Stoffer M., Takeuchi T., Aletaha D., Andreu J., Aringer M., Bergman M., Betteridge N., Bijlsma H., Burkhardt H., Cardiel M., Combe B., Durez P., Fonseca J., Gibofsky A., Gomez-Reino J., Graninger W., Hannonen P., Haraoui B., Kouloumas M., Landewe R., Martin-Mola E., Nash P., Ostergaard M., Östör A., Richards P., Sokka-Isler T., Thorne C., Tzioufas A., van Vollenhoven R., de Wit M., van der Heijde D.

Annals of the rheumatic diseases （Annals of the rheumatic diseases） 75 （ 1 ） 3 - 15 2016年01月

研究論文（学術雑誌）, 査読有り

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/ BACKGROUND: Reaching the therapeutic target of remission or low-disease activity has improved outcomes in patients with rheumatoid arthritis (RA) significantly. The treat-to-target recommendations, formulated in 2010, have provided a basis for implementation of a strategic approach towards this therapeutic goal in routine clinical practice, but these recommendations need to be re-evaluated for appropriateness and practicability in the light of new insights.OBJECTIVE: To update the 2010 treat-to-target recommendations based on systematic literature reviews (SLR) and expert opinion.METHODS: A task force of rheumatologists, patients and a nurse specialist assessed the SLR results and evaluated the individual items of the 2010 recommendations accordingly, reformulating many of the items. These were subsequently discussed, amended and voted upon by >40 experts, including 5 patients, from various regions of the world. Levels of evidence, strengths of recommendations and levels of agreement were derived.RESULTS: The update resulted in 4 overarching principles and 10 recommendations. The previous recommendations were partly adapted and their order changed as deemed appropriate in terms of importance in the view of the experts. The SLR had now provided also data for the effectiveness of targeting low-disease activity or remission in established rather than only early disease. The role of comorbidities, including their potential to preclude treatment intensification, was highlighted more strongly than before. The treatment aim was again defined as remission with low-disease activity being an alternative goal especially in patients with long-standing disease. Regular follow-up (every 1-3 months during active disease) with according therapeutic adaptations to reach the desired state was recommended. Follow-up examinations ought to employ composite measures of disease activity that include joint counts. Additional items provide further details for particular aspects of the disease, especially comorbidity and shared decision-making with the patient. Levels of evidence had increased for many items compared with the 2010 recommendations, and levels of agreement were very high for most of the individual recommendations (≥9/10).CONCLUSIONS: The 4 overarching principles and 10 recommendations are based on stronger evidence than before and are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA.

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Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force

Annals of the Rheumatic Diseases （Annals of the Rheumatic Diseases） 75 （ 1 ） 3 - 15 2016年01月

研究論文（学術雑誌）, 査読有り, ISSN 00034967

Background: Reaching the therapeutic target of remission or low-disease activity has improved outcomes in patients with rheumatoid arthritis (RA) significantly. The treat-to-target recommendations, formulated in 2010, have provided a basis for implementation of a strategic approach towards this therapeutic goal in routine clinical practice, but these recommendations need to be re-evaluated for appropriateness and practicability in the light of new insights. Objective: To update the 2010 treat-to-target recommendations based on systematic literature reviews (SLR) and expert opinion. Methods: A task force of rheumatologists, patients and a nurse specialist assessed the SLR results and evaluated the individual items of the 2010 recommendations accordingly, reformulating many of the items. These were subsequently discussed, amended and voted upon by >40 experts, including 5 patients, from various regions of the world. Levels of evidence, strengths of recommendations and levels of agreement were derived. Results: The update resulted in 4 overarching principles and 10 recommendations. The previous recommendations were partly adapted and their order changed as deemed appropriate in terms of importance in the view of the experts. The SLR had now provided also data for the effectiveness of targeting low-disease activity or remission in established rather than only early disease. The role of comorbidities, including their potential to preclude treatment intensification, was highlighted more strongly than before. The treatment aim was again defined as remission with low-disease activity being an alternative goal especially in patients with long-standing disease. Regular follow-up (every 1-3 months during active disease) with according therapeutic adaptations to reach the desired state was recommended. Follow-up examinations ought to employ composite measures of disease activity that include joint counts. Additional items provide further details for particular aspects of the disease, especially comorbidity and shared decision-making with the patient. Levels of evidence had increased for many items compared with the 2010 recommendations, and levels of agreement were very high for most of the individual recommendations (≥9/10). Conclusions: The 4 overarching principles and 10 recommendations are based on stronger evidence than before and are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA.

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A unique case of polymyositis with anti-signal recognition particle antibody complicated by subacute interstitial lung disease and subluxing arthropathy, resembling anti-synthetase syndrome

Hanaoka Hironari, Kaneko Yuko, Suzuki Shigeaki, Takada Tetsuya, Hirakata Michito, Takeuchi Tsutomu, Kuwana Masataka

Modern Rheumatology 26 978 - 979 2016年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

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Time lag between the initiation of adalimumab after methotrexate correlates with the efficacy of adalimumab in rheumatoid arthritis patients

Kimura N., Suzuki K., Takeuchi T.

Modern Rheumatology （Modern Rheumatology） 27 （ 5 ） 676 - 680 2015年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2016 Japan College of Rheumatology. Objectives: To evaluate the efficacy and safety of adalimumab (ADA) and methotrexate (MTX) in patients with rheumatoid arthritis (RA) and investigate critical factors associated with efficacy. Methods: In this retrospective cohort study, patients received ADA at a single facility. Clinical outcome was retrospectively evaluated using the Disease Activity Score in 28 joints with Erythrocyte Sedimentation Rate (DAS28-ESR). Results: Of the 122 patients undergoing treatment with ADA between July 2008 and April 2014, DAS28-ESR data after 6 months of treatment were available for 103 and 87 (84.5%) were treated with a combination of ADA and MTX. For combination therapy, time lag between MTX and the initiation of ADA significantly correlated with efficacy of ADA at 6 months, as well as prior use of biologics, but not disease duration. Conclusions: Clinical outcomes were correlated with the time lag between MTX and the initiation of ADA, not disease duration. Early initiation of ADA after MTX might improve clinical outcomes.

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Baseline serum osteopontin levels predict the clinical effectiveness of tocilizumab but not infliximab in biologic-Naïve patients with rheumatoid arthritis: A single-center prospective study at 1 year (the Keio First-Bio Cohort study)

Izumi K., Kaneko Y., Hashizume M., Yoshimoto K., Takeuchi T.

PLoS ONE （PLoS ONE） 10 （ 12 ） e0145468 2015年12月

研究論文（学術雑誌）, 共著, 査読有り

© 2015 Izumi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Objective: To explore the baseline predictors of clinical effectiveness after tocilizumab or infliximab treatment in biologic-naïve rheumatoid arthritis patients. Methods: Consecutive biologic-naïve patients with rheumatoid arthritis initiating infliximab (n = 57) or tocilizumab (n = 70) treatment were included in our prospective cohort study. Our cohort started in February 2010, and the patients observed for at least 1 year as of April 2013 were analysed. We assessed baseline variables including patients' characteristics (age, sex, disease duration, prednisolone dose, methotrexate dose, other disease-modifying antirheumatic drug use, Clinical Disease Activity Index [CDAI]) and serum biomarker levels (C-reactive protein, immunoglobulin M-rheumatoid factor, anti-cyclic citrullinated protein/pep-tide antibodies, interferon-y, interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-10, IL-17, tumor necrosis factor-a, soluble intercellular adhesion molecule-1, bone alkaline phosphatase, osteonectin, osteopontin) to extract factors associated with clinical remission (CDAK2.8) at 1 year using univariate analyses, and the extracted factors were entered into a multivariate logistic regression model. Similar analyses were also performed for Simplified Disease Activity Index (SDAI) remission (<3.3) and Disease Activity Score with 28 joint counts, erythrocyte sedimentation rate (DAS28-ESR) remission (<2.6).

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The "treat-to-target" strategies for rheumatoid arthritis and managing for bone cartilage destructions

Kondo Y., Kaneko Y., Takeuchi T.

Clinical calcium （Clinical calcium） 25 （ 12 ） 1757 - 1762 2015年12月

研究論文（学術雑誌）, 査読有り, ISSN 09175857

Sometime ago, there was little choice for the treatment of rheumatoid arthritis(RA)that was regarded as an untreateble disease but supportive analgesics and mild disease modified drugs. The advent of biological agents with abundant clinical researches regarding remarkable efficacy has cased dramatically the paradigm shift in the treatment of RA. The strategy for medical care to RA has now entered a new era in that treatment target should be clarified and shared between patient and rheumatologist aiming the prevention of structural damage and the maintain of long-term quality of life(QOL)by tight-control. In this review, we summarize the "treat to target"(T2T)strategies for RA and its impact to manage for bone and cartilage destructions.

Successful resumption of tocilizumab for rheumatoid arthritis after resection of a pulmonary Mycobacterium avium complex lesion: A case report

Namkoong H., Tasaka S., Akiyama M., Yagi K., Ishii M., Suzuki K., Kohno M., Hasegawa N., Takeuchi T., Betsuyaku T.

BMC Pulmonary Medicine （BMC Pulmonary Medicine） 15 （ 1 ） 2015年10月

研究論文（学術雑誌）, 共著, 査読有り

© 2015 Namkoong et al. Background: Biological agents inhibiting TNF-aα and other molecules involved in inflammatory cascade have been increasingly used to treat rheumatoid arthritis (RA). However, it remains controversial whether biological agents can be used safely in a patient with an underlying chronic infectious disease. Case presentation: A 63-year-old woman who had been treated with tocilizumab (TCZ), anti-interleukin-6 receptor antibody, for RA presented to our outpatient clinic due to hemoptysis. She was diagnosed with pulmonary Mycobacterium avium complex (MAC) infection, and high-resolution computed tomography (HRCT) showed a single cavitary lesion in the right upper lobe. After diagnosis of pulmonary MAC disease, TCZ was discontinued and combination chemotherapy with clarithromycin, rifampicin, ethambutol and amikacin was started for MAC pulmonary disease. Since the lesion was limited in the right upper lobe as a single cavity formation, she underwent right upper lobectomy. As her RA symptoms were deteriorated around the operation, TCZ was resumed. After resumption of TCZ, her RA symptoms improved and a recurrence of pulmonary MAC infection has not been observed for more than 1 year. Conclusion: This case suggested that TCZ could be safely reintroduced after the resection of a pulmonary MAC lesion. Although the use of biological agents is generally contraindicated in patients with pulmonary MAC disease, especially in those with a fibrocavitary lesion, a multimodality intervention for MAC including both medical and surgical approaches may enable introduction or resumption of biological agents.

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