研究者詳細 - 竹内　勤

論文 - 竹内　勤

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Evaluation of the alternative classification criteria of systemic lupus erythematosus established by Systemic Lupus International Collaborating Clinics (SLICC)

竹内勤

Modern Rheumatology （Modern Rheumatology） 28 （ 4 ） 642 - 648 2017年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 14397595

© 2017, © 2017 Japan College of Rheumatology. Objective: To evaluate the performance of the 2012 Systemic Lupus International Collaborating Clinics criteria (SLICC-12) on classifying systemic lupus erythematosus (SLE) in an uncontrolled multi-centered study with real-life scenario of the patients in Japan. Methods: This study comprised 495 patients with SLE or non-SLE rheumatic diseases and allied conditions from 12 institutes in Japan. Chart review of each patient was performed by the 27 expert rheumatologists and diagnosis of 487 cases reached to the consensus. Value of the SLICC-12 on SLE classification was analyzed comparing with the 1997 revised American College of Rheumatology SLE classification criteria (ACR-97) employing the expert-consented diagnoses. Results: Compared to the ACR-97, the SLICC-12 had a higher sensitivity (ACR-97 vs. SLICC-12: 0.88 vs. 0.99, p <.01) and comparable specificity (0.85 vs. 0.80). The rate of misclassification (0.14 vs. 0.11) or the area under the receiver operating characteristic curves (0.863 vs. 0.894) was not statistically different. In the cases that diagnoses corresponded in high rates among experts, both criteria showed high accordance of SLE classification over 85% with the expert diagnoses. Conclusion: Although employment of SLICC-12 for the classification for SLE should be carefully considered, the SLICC-12 showed the higher sensitivity on classifying SLE in Japanese population.

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Targeted antibody therapy and relevant novel biomarkers for precision medicine for rheumatoid arthritis

Kaneko Y., Takeuchi T.

International Immunology （International Immunology） 29 （ 11 ） 511 - 517 2017年11月

研究論文（学術雑誌）, 査読有り, ISSN 09538178

© The Japanese Society for Immunology. 2017. Over the past two decades, the management of rheumatoid arthritis (RA) has progressed remarkably, encompassing the development of new diagnostic tools and efficacious biological agents, such as monoclonal antibodies against inflammatory cytokines and surface markers on immune cells. In addition to the significant efficacy of these biological agents, biomarkers for RA are under consideration for their potential to classify heterogeneous patients into several groups based on clinical and immunological phenotypes for the prediction of clinical course and prognosis and the facilitation of appropriate and precise treatment with the appropriate therapeutic monoclonal antibodies. Biomarkers, particularly those for the prediction and monitoring of the responses to therapeutic monoclonal antibodies for RA, are in demand, with many approaches examined in recent years. In this article, we have summarized the background research on biomarkers and introduced recent topics in the field that enable the possible clinical applications of biomarkers, especially those related to pathogenic cytokines, to guide the treatment of RA.

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A new bioassay for measuring the strength of IL-6/STAT3 signal inhibition by tocilizumab in patients with rheumatoid arthritis

Saito S., Suzuki K., Yoshimoto K., Kaneko Y., Matsumoto Y., Yamaoka K., Takeuchi T.

Arthritis Research and Therapy （Arthritis Research and Therapy） 19 （ 1 ） 2017年10月

研究論文（学術雑誌）, 査読有り, ISSN 14786354

© 2017 The Author(s). Background: Interleukin-6 (IL-6) transduces signals via phosphorylation of STAT3 (pSTAT3). Tocilizumab (TCZ) is an IL-6 receptor blocker, which, when administered intravenously every 4 weeks, efficiently ameliorates rheumatoid arthritis (RA). Since IL-6 signal strength varies among patients with RA, the intensity necessary for appropriate IL-6 signal inhibition by TCZ might vary between individuals. In a previous study, we have examined the clinical utility of increasing (dosing interval shortened to 3 weeks) and decreasing (interval extended to 5 weeks) the dose frequency of TCZ. However, there is currently no established method for accurately measuring the strength of IL-6 signal inhibition by TCZ among individual patients. We therefore sought to develop such an assay. Methods: Whole blood samples were collected from RA patients with low disease activity (clinical disease activity index (CDAI)≤10) who were treated with TCZ at dosing intervals of 3 weeks (3-week group, n=10), 4 weeks (4-week group, n=10) or 5 weeks (5-week group, n=10), or with methotrexate (control group, n=10). Recombinant human IL-6 (0, 0.1, 1, 10, 100 ng/ml) was exogenously added to whole blood and the proportion of pSTAT3-positive CD4+ T cells (%pSTAT3+/CD4+) was measured by Phosflow cytometric analysis. Results: The addition of exogenous IL-6 increased the proportion of pSTAT3-positive CD4+ T cells in a dose-dependent manner in each group. Inhibition of IL-6 signaling was strongest in the 3-week dosing group, followed by the 4-week, 5-week and control group. Significant differences in %pSTAT3+/CD4+ cells were observed between dose interval groups when stimulated with 10 ng/ml and 100 ng/ml of IL-6. Conclusion: Assessment of the proportion of pSTAT3-positive CD4+ T cells under IL-6 stimulation is a highly sensitive and useful method for determining differences in the strength of IL-6 signal inhibition in patients treated with TCZ. It is suggested that different TCZ treatment intervals were necessary to lower disease activity in each group of patients, and these findings also indicate that the IL-6 signaling pathway may differ in each RA patient. Our assay may support strategies for optimizing TCZ treatment in RA patients.

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CC-chemokine ligand 18 is a useful biomarker associated with disease activity in IgG4-related disease

竹内勤

Annals of the Rheumatic Diseases 2017年10月

研究論文（学術雑誌）, 共著, 査読有り

Risk factors for the recurrence of interstitial lung disease in patients with polymyositis and dermatomyositis: a retrospective cohort study

竹内勤

Clinical Rheumatology （Clinical Rheumatology） 37 （ 3 ） 765 - 771 2017年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 07703198

© 2017, International League of Associations for Rheumatology (ILAR). To identify risk factors for the recurrence of interstitial lung disease (ILD) in patients with polymyositis (PM)/dermatomyositis (DM). Forty-four PM/DM-ILD patients who had been treated with glucocorticoid and/or immunosuppressive agents as a remission induction therapy were enrolled. The patients were first classified into two groups: the early recurrence group that recurred within 52 weeks, and the non-early recurrence group, which was further classified into the late recurrence group that recurred after 52 weeks, and the non-recurrence group. The characteristics and treatment regimen between the groups were compared. Recurrence was experienced by 15 of 44 patients. The pulmonary vital capacity of the early recurrence group was significantly lower than the non-early recurrence group (46 vs 76%, p = 0.0003), and 60% of the early recurrence group was treated with glucocorticoid alone as a maintenance therapy in contrast to 10% in the non-early recurrence group (p = 0.004). The late recurrence was only related with a positivity for autoantibodies against aminoacyl-tRNA synthetases (anti-ARS antibodies, odds ratio 8.4, p = 0.02), but calcineurin inhibitors tended to decrease the relapse incidence in patients with anti-ARS antibodies. Low pulmonary vital capacity at disease onset and anti-ARS antibodies positivity are the risk factors for the recurrence of ILD with PM/DM. Calcinuerin inhibitors are important in preventing relapse.

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Targeted proteomics reveals promising biomarkers of disease activity and organ involvement in antineutrophil cytoplasmic antibody-associated vasculitis

Ishizaki J., Takemori A., Suemori K., Matsumoto T., Akita Y., Sada K., Yuzawa Y., Amano K., Takasaki Y., Harigai M., Arimura Y., Makino H., Yasukawa M., Takemori N., Hasegawa H., Murakawa Y., Muso E., Komatsuda A., Ito S., Fujii T., Kawakami A., Nakaya I., Saito T., Ito T., Hirawa N., Yamamura M., Nakano M., Nitta K., Ogura M., Naniwa T., Ozaki S., Hirahashi J., Ogawa N., Hosoya T., Wada T., Horikoshi S., Kawaguchi Y., Hayashi T., Yoshida M., Watanabe T., Inaguma D., Tsuruya K., Homma N., Takeuchi T., Nakagawa N., Takeda S., Katabuchi R., Iwano M., Atsumi T., Fujimoto S., Banno S., Sugihara T., Kobayashi M., Yamagata K., Homma S., Dobashi H., Tsuboi N., Ishizu A., Sugiyama H.

Arthritis Research and Therapy （Arthritis Research and Therapy） 19 （ 1 ） 2017年09月

研究論文（学術雑誌）, 査読有り, ISSN 14786354

© 2017 The Author(s). Background: Targeted proteomics, which involves quantitative analysis of targeted proteins using selected reaction monitoring (SRM) mass spectrometry, has emerged as a new methodology for discovery of clinical biomarkers. In this study, we used targeted serum proteomics to identify circulating biomarkers for prediction of disease activity and organ involvement in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Methods: A large-scale SRM assay targeting 135 biomarker candidates was established using a triple-quadrupole mass spectrometer coupled with nanoflow liquid chromatography. Target proteins in serum samples from patients in the active and remission (6 months after treatment) stages were quantified using the established assays. Identified marker candidates were further validated by enzyme-linked immunosorbent assay using serum samples (n = 169) collected in a large-cohort Japanese study (the RemIT-JAV-RPGN study). Results: Our proteomic analysis identified the following proteins as biomarkers for discriminating patients with highly active AAV from those in remission or healthy control subjects: tenascin C (TNC), C-reactive protein (CRP), tissue inhibitor of metalloproteinase 1 (TIMP1), leucine-rich alpha-2-glycoprotein 1, S100A8/A9, CD93, matrix metalloproteinase 9, and transketolase (TKT). Of these, TIMP1 was the best-performing marker of disease activity, allowing distinction between mildly active AAV and remission. Moreover, in contrast to CRP, serum levels of TIMP1 in patients with active AAV were significantly higher than those in patients with infectious diseases. The serum levels of TKT and CD93 were higher in patients with renal involvement than in those without, and they predicted kidney outcome. The level of circulating TNC was elevated significantly in patients with lung infiltration. AAV severity was associated with markers reflecting organ involvement (TKT, CD93, and TNC) rather than inflammation. The eight markers and myeloperoxidase (MPO)-ANCA were clustered into three groups: MPO-ANCA, renal involvement (TKT and CD93), and inflammation (the other six markers). Conclusions: We have identified promising biomarkers of disease activity, disease severity, and organ involvement in AAV with a targeted proteomics approach using serum samples obtained from a large-cohort Japanese study. Especially, our analysis demonstrated the effectiveness of TIMP1 as a marker of AAV activity. In addition, we identified TKT and CD93 as novel markers for evaluation of renal involvement and kidney outcome in AAV.

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Patient-reported outcomes of baricitinib in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment

Schiff M., Takeuchi T., Fleischmann R., Gaich C., DeLozier A., Schlichting D., Kuo W., Won J., Carmack T., Rooney T., Durez P., Shaikh S., Hidalgo R., van Vollenhoven R., Zerbini C.

Arthritis Research and Therapy （Arthritis Research and Therapy） 19 （ 1 ） 2017年09月

研究論文（学術雑誌）, 査読有り, ISSN 14786354

© 2017 The Author(s). Background: This study evaluates patient-reported outcomes (PROs) in a double-blind, phase III study of baricitinib as monotherapy or combined with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) with no or minimal prior conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and naïve to biological DMARDs. Methods: Patients were randomized 4:3:4 to MTX administered once weekly (N = 210), baricitinib monotherapy (4 mg once daily (QD), N = 159), or combination of baricitinib (4 mg QD) and MTX (baricitinib + MTX, N = 215). PROs included the Patient's Global Assessment of Disease Activity (PtGA), patient's assessment of pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), duration of morning joint stiffness (MJS), worst joint pain, worst tiredness, Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA), Short Form 36 version 2, Acute (SF-36); and EuroQol 5-Dimensions (EQ-5D) Health State Profile. Comparisons were assessed with analysis of covariance (ANCOVA) and logistic regression models. Results: Compared to MTX, patients in both baricitinib groups reported greater improvement (p ≤ 0.01) in HAQ-DI, PtGA, pain, fatigue, worst join pain, SF-36 physical component score, and EQ-5D at weeks 24 and 52. For the SF-36 mental component score, patients in both baricitinib groups reported statistically significant improvements (p ≤ 0.01) at week 52 compared to MTX-treated patients. Statistically significant improvements (p ≤ 0.05) were observed with the WPAI-RA for the baricitinib groups vs. MTX at week 24 and for the WPAI-RA daily activity and work productivity measures for baricitinib + MTX at week 52. Conclusions: In this study, baricitinib alone or in combination with MTX, when used as initial therapy, resulted in significant improvement compared to MTX in the majority of the pre-specified PRO measures. Trial Registration: ClinicalTrials.gov, NCT01711359. Registered on 18 October 2012.

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

竹内勤

Circulation Journal 2017年09月

研究論文（学術雑誌）, 共著, 査読有り

High titers of both rheumatoid factor and anti-CCP antibodies at baseline in patients with rheumatoid arthritis are associated with increased circulating baseline TNF level, low drug levels, and reduced clinical responses: A post hoc analysis of the RISING study

竹内勤

Arthritis Research and Therapy （Arthritis Research and Therapy） 19 （ 1 ） 194 2017年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 14786354

© 2017 The Author(s). Background: Although both rheumatoid factor (RF) and anticyclic citrullinated peptide antibodies (anti-CCP) are useful for diagnosing rheumatoid arthritis (RA), the impact of these autoantibodies on the efficacy of tumor necrosis factor (TNF) inhibitors has been controversial. The aim of this post hoc analysis of a randomized double-blind study (the RISING study) was to investigate the influences of RF and anti-CCP on the clinical response to infliximab in patients with RA. Methods: Methotrexate-refractory patients with RA received 3 mg/kg of infliximab from weeks 0 to 6 and then 3, 6, or 10 mg/kg every 8 weeks from weeks 14 to 46. In this post hoc analysis, patients were stratified into three classes on the basis of baseline RF/anti-CCP titers: "low/low-C" (RF < 55 IU/ml, anti-CCP < 42 U/ml), "high/high-C" (RF ≥ 160 IU/ml, anti-CCP ≥ 100 U/ml), and "middle-C" (neither low/low-C nor high/high-C). Baseline plasma TNF level, serum infliximab level, and disease activity were compared between the three classes. Results: Baseline RF and anti-CCP titers showed significant correlations with baseline TNF and infliximab levels in weeks 2-14. Comparison of the three classes showed that baseline TNF level was lowest in the low/low-C group and highest in the high/high-C group (median 0.73 versus 1.15 pg/ml), that infliximab levels at week 14 were highest in the low/low-C group and lowest in the high/high-C group (median 1.0 versus 0.1 μg/ml), and that Disease Activity Score in 28 joints based on C-reactive protein at week 14 was lowest in the low/low-C group and highest in the high/high-C group (median 3.17 versus 3.82). A similar correlation was observed at week 54 in the 3 mg/kg dosing group, but not in the 6 or 10 mg/kg group. Significant decreases in both RF and anti-CCP were observed during infliximab treatment. Conclusions: RF/anti-CCP titers correlated with TNF level. This might explain the association of RF/anti-CCP with infliximab level and clinical response in patients with RA. Baseline RF/anti-CCP titers may serve as indices that aid infliximab treatment. Trial registration: ClinicalTrials.gov, NCT00691028. Retrospectively registered on 3 June 2008.

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Sirukumab for rheumatoid arthritis: The phase III SIRROUND-D study

竹内勤

Annals of the Rheumatic Diseases （Annals of the Rheumatic Diseases） 76 （ 12 ） 2001 - 2008 2017年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1468-2060

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted. Objectives Interleukin-6 (IL-6) is implicated in rheumatoid arthritis (RA) pathophysiology. Unlike IL-6 receptor inhibitors, sirukumab is a human monoclonal antibody that selectively binds to the IL-6 cytokine. The phase III, multicentre, randomised, double-blind, placebo-controlled, parallel-group SIRROUND-D study (ClinicalTrials.gov identifier NCT01604343) evaluated the efficacy and safety of sirukumab in patients with active RA refractory to disease-modifying antirheumatic drugs. Methods Patients were randomised 1:1:1 to treatment with sirukumab 100 mg every 2 weeks, 50 mg every 4 weeks or placebo every 2 weeks subcutaneously. Results through week 52 are reported. Results Of 1670 randomised patients, significantly more patients achieved American College of Rheumatology 20% (ACR20) response at week 16 (coprimary endpoint) with sirukumab 100 mg every 2 weeks (53.5%) or 50 mg every 4 weeks (54.8%) versus placebo (26.4%; both p<0.001). Mean (SD) change from baseline in modified Sharp/van der Heijde score at week 52 (coprimary endpoint) was significantly lower with sirukumab (100 mg every 2 weeks: 0.46 (3.26); 50 mg every 4 weeks: 0.50 (2.96)) versus placebo (3.69 (9.25); both p<0.001). All major secondary endpoints (week 24 Health Assessment Questionnaire-Disability Index change from baseline, ACR50 response, 28-joint Disease Activity Score based on C reactive protein and major clinical response (ACR70 for six continuous months by week 52)) were met. The most common adverse events with sirukumab were elevated liver enzymes, upper respiratory tract infection, injection site erythema and nasopharyngitis. Conclusions Sirukumab 100 mg every 2 weeks and 50 mg every 4 weeks led to significant reductions in RA symptoms, inhibition of structural damage progression and physical function and quality of life improvements, with an expected safety profile. Trial registration number NCT01604343; Results.

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Treatment efficacy and methotrexate-related toxicity in patients with rheumatoid arthritis receiving methotrexate in combination with adalimumab

Burmester G., Kaeley G., Kavanaugh A., Gabay C., MacCarter D., Nash P., Takeuchi T., Goss S., Rodila R., Chen K., Kupper H., Kalabic J.

RMD Open （RMD Open） 3 （ 2 ） 2017年09月

研究論文（学術雑誌）, 査読有り

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted. Background Treatment of rheumatoid arthritis (RA) with a combination of methotrexate (MTX)+adalimumab (ADA) is more effective than ADA monotherapy. We assessed the toxicity of different doses of MTX and treatment efficacy of ADA+MTX in two trials. Methods Data originated from CONCERTO, in patients with early RA initiating ADA+ 2.5, 5, 10 or 20 mg/week MTX for 26 weeks; and MUSICA, in patients with an inadequate response to MTX initiating ADA+ 7.5 or 20 mg/week MTX for 24 weeks. Efficacy was assessed by the American College of Rheumatology 50 (ACR50). Patient-reported MTX-related toxicity information was collected at each visit on 18 prespecified MTX-related adverse events (AE) in the MTX label. Results In CONCERTO, ACR50 rates increased over time, ranging from 54% to 68% at week 26, while AE rates remained steady, ranging from 2.4% to 17.8% at week 26. Of 395 patients, 113 (28.6%) reported 345 MTX-related AEs, including one serious AE (SAE, excessive fatigue and/or malaise); 10 AEs (in two patients) led to study discontinuation. In MUSICA, ACR50 rates increased over time, and were 32.3% and 37.5% at week 24, while MTX-related AE rates remained steady and were 6.5% at week 24. Of 309 patients, 71 (23%) reported 185 MTX-related AEs, including 5 SAEs (four infections and one fever/chills); six AEs (in four patients) led to study discontinuation. Conclusion In patients with RA initiating ADA+MTX combination, treatment efficacy was achieved and increased throughout both trials, while rates of MTX-related AEs remained steady. MTX-related AEs were observed in up to 30% of patients and most were mild. MTX was discontinued by 0.5%-1.3% of patients. Trial registration number MUSICA (NCT01185288), CONCERTO (NCT01185301), Post results.

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Comparison of the Clinical Characteristics of Pneumocystis Pneumonia between Patients with Rheumatoid Arthritis Being Treated with Biologics and Those Being Treated without Biologics

Akiyama M., Kaneko Y., Takeuchi T.

BioMed Research International （BioMed Research International） 2017 3710652 2017年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2314-6133

© 2017 Mitsuhiro Akiyama et al. Objective. The aim of this study was to compare the clinical characteristics of pneumocystis pneumonia (PCP) between patients with rheumatoid arthritis (RA) being treated with biologics and those being treated without biologics. Methods. From 8,630 patients with RA in our institution, we enrolled 24 patients who had developed PCP during the course of their treatment. They were divided into two groups according to the treatment they were receiving for RA: the biologics group (n=12) and the nonbiologics group (n=12). Clinical characteristics of PCP were compared between the two groups. Results. At PCP diagnosis, the biologics group showed significantly lower serum levels of β-D-glucan and C-reactive protein than the nonbiologics group, while the biologics group had significantly higher lymphocyte counts than the nonbiologics group. In the nonbiologics group, lower lymphocyte counts were associated with higher β-D-glucan levels; however, this was not observed in the biologics group. Conclusion. The finding that RA patients being treated with biologics developed PCP with relatively normal lymphocyte counts and lower β-D-glucan levels suggests that the pathophysiology of PCP in those patients is different from that in patients being treated with other antirheumatic drugs.

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Effectiveness and safety of tocilizumab in achieving clinical and functional remission, and sustaining efficacy in biologics-naive patients with rheumatoid arthritis: The FIRST Bio study

竹内勤

Modern Rheumatology （Modern Rheumatology） 27 （ 2 ） 217 - 226 2017年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 14397595

© 2016 Japan College of Rheumatology. Published by Informa UK Limited, trading as Taylor & Francis Group. Objective: To evaluate effectiveness and safety of tocilizumab (TCZ) in biologic-naive Japanese patients with rheumatoid arthritis (RA) in real-world settings, and to analyze the relationship between disease duration and clinical outcomes. Methods: The FIRST Bio study was a postmarketing surveillance study of intravenous TCZ in biologics-naive patients who had a prior inadequate response or were intolerant to ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD). Effectiveness, safety, and concomitant csDMARD administration were assessed. Results: Of the 839 patients analyzed, 72.3% completed 52 weeks of treatment. The Clinical Disease Activity Index (CDAI) remission rate at week 52 was 36.8%. Contributing factors for CDAI remission were younger age, early disease stage, and no comorbidities. Health Assessment Questionnaire Disability Index ≤0.5 was achieved in 65.1% of patients, and was significantly associated with disease duration. Discontinuation of concomitant methotrexate (MTX) and glucocorticoids (GCs) was possible in 19.3% and 34.1% of patients, respectively, without decreasing remission rate. The incidence (events/100 patient-years) of serious adverse events was 18.09, the most common being infection. Conclusion: These data validate the importance of TCZ treatment in the early stages of RA in biologic-naive patients to achieve increased effectiveness. The safety profile of TCZ was reconfirmed. Furthermore, TCZ therapy may allow discontinuation of concomitant MTX and GCs without affecting remission.

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Distinct features distinguishing IgG4-related disease from multicentric Castleman's disease

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

RMD Open （RMD Open） 3 （ 1 ） e000432 2017年07月

研究論文（学術雑誌）, 共著, 査読有り

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted. Objectives Differentiating IgG4-related disease (IgG4-RD) from multicentric Castleman's disease (MCD) is challenging because both diseases present high serum IgG4. The objective of this study is to clarify the differences in characteristics and identify a clinically useful approach to differentiate these two diseases. Methods Forty-five consecutive patients with untreated active IgG4-RD and 33 patients with MCD were included in this study, who visited our institution from January 2000 to August 2016. The clinical and laboratory findings for the patients of the two diseases were compared. Various combinations of the distinctive findings were evaluated to identify the most efficient differentiating features between IgG4-RD and MCD. Results The levels of serum IgG4 were not different between the two diseases. Orbits, lacrimal glands, salivary glands or pancreas were involved in 88.9% of IgG4-RD cases and only in 3.0% of MCD cases. All MCD cases involved lymph nodes. Atopic history was characteristic for IgG4-RD. The levels of C reactive protein (CRP) with a cut-off of 0.80 mg/dL and IgA with a cut-off of 330 mg/dL were the most distinctive. The combination of â € Orbits, lacrimal glands, salivary glands or pancreas involvement, atopic history, or non-involvement of lymph node' and â € CRP ≤ 0.8 mg/dL or IgA ≤ 330 mg/dL' yielded the probability of 97.8% in IgG4-RD, while that of 3.0 % in patients with MCD. Conclusions Our study revealed distinct features between IgG4-RD and MCD. Differentiating between the diseases based on those distinct features, including distribution of organ involvement, atopic history, levels of IgA and CRP, was a useful approach.

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Pre-treatment interleukin-6 levels strongly affect bone erosion progression and repair detected by magnetic resonance imaging in rheumatoid arthritis patients

Kondo Y., Kaneko Y., Sugiura H., Matsumoto S., Nishina N., Kuwana M., Jinzaki M., Takeuchi T.

Rheumatology (United Kingdom) （Rheumatology (United Kingdom)） 56 （ 7 ） 1089 - 1094 2017年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1462-0324

© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. Objective. To examine the relationship between MRI structural damage and repair and plasma inflammatory cytokines in patients with RA. Methods. A total of 88 newly diagnosed, untreated RA patients were enrolled. Contrast MRI of the dominant hand and X-rays of the hands and feet were performed at baseline and 1 year later. MR images were evaluated using RA MRI scoring, and X-raywere assessed by the modified total Sharp score. Erosion progression was defined as changes in RA MRI scoring erosion or modified total Sharp score erosion of >0.5. Erosion repair was defined as erosion score changes of less than -0.5. Plasma levels of 10 cytokines were measured by electrochemiluminescence assay. Results. Progression of bone erosion and repair were observed more frequently in MRI than in X-rays (erosion, 52% vs 26%, P < 0.001; repair, 26% vs 15%, P = 0.003, respectively). Baseline IL-6 levels and seropositivity were independent relevant factors for MRI erosion progression, with IL-6 having stronger effect than seropositivity. A receiver operating characteristic curve identified the baseline IL-6 level of 7.6 pg/ml for predicting erosion progression during 1 year, with an area under the curve of 0.82; higher IL-6 levels resulted in more erosion progression. Baseline low IL-6 was also an independent predictor for MRI erosion repair. Conclusion. In newly diagnosed, untreated RA patients, baseline plasma IL-6 levels are responsible for 1-year MRI bone erosion progression and repair.

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Immunogenicity of Biologics in Chronic Inflammatory Diseases: A Systematic Review

竹内勤

BioDrugs （BioDrugs） 31 （ 4 ） 299 - 316 2017年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 11738804

© 2017, The Author(s). Objectives: A systematic review was conducted to explore the immunogenicity of biologic agents across inflammatory diseases and its potential impact on efficacy/safety. Methods: Literature searches were conducted through November 2016 to identify controlled and observational studies of biologics/biosimilars administered for treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS), non-radiographic axial spondyloarthritis (nr-axSpA), psoriasis (Ps), Crohn’s disease, and ulcerative colitis. Results: Of >21,000 screened publications, 443 were included. Anti-drug antibody (ADAb) rates varied widely among biologics across diseases (and are not directly comparable because of immunoassay heterogeneity); the highest overall rates were reported with infliximab (0–83%), adalimumab (0–54%), and infliximab biosimilar CT-P13 (21–52%), and the lowest with secukinumab (0–1%), ustekinumab (1–11%), etanercept (0–13%), and golimumab (0–19%). Most ADAbs were neutralizing, except those to abatacept and etanercept. ADAb+ versus ADAb− patients had lower rates of clinical response to adalimumab (RA, PsA, JIA, AS, Ps), golimumab (RA), infliximab (RA, PsA, AS, Ps), rituximab (RA), ustekinumab (Ps), and CT-P13 (RA, AS). Higher rates of infusion-related reactions were reported in infliximab- and CT-P13-treated ADAb+ patients. Background immunosuppressives/anti-proliferatives reduced biologic immunogenicity across diseases. Conclusions: Based on reviewed reports, biologic/biosimilar immunogenicity differs among agents, with the highest rates observed with infliximab and adalimumab. As ADAb formation in biologic-/biosimilar-treated patients may increase the risk of lost response, the immunogenicity of these agents is an important (albeit not the only) consideration in the treatment decision-making process.

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Distinct patterns of lymphocyte count transition in lymphoproliferative disorder in patients with rheumatoid arthritis treated with methotrexate

Saito S., Kaneko Y., Yamaoka K., Tokuhira M., Takeuchi T.

Rheumatology (United Kingdom) （Rheumatology (United Kingdom)） 56 （ 6 ） 940 - 946 2017年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1462-0324

© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. Objective. To clarify the characteristics of lymphoproliferative disorder (LPD) in patients with RA treated with MTX. Methods. Among 33 patients developing LPD during MTX treatment, 20 LPDs regressed spontaneously within 12 weeks after MTX cessation (regressive LPD), and 13 did not regress and most of them died or needed chemotherapy (persistent LPD). The control group consisted of 66 clinically matched MTX-treated RA patients without LPD. The clinical characteristics were compared between these three groups. Results. While no significant differences were found in clinical RA and LPD features among the three groups, the absolute lymphocyte number of the two LPD groups at LPD diagnosis was significantly lower than the control group (497/μl in the regressive vs 680/μl in the persistent vs 1400/μl in the control, P<0.05). After MTX withdrawal, the lymphocyte number in the regressive group rapidly recovered to 1214/μl (P<0.01) by week 2 and was thereafter maintained at an equivalent level to the control group. In contrast, lymphocyte level in the persistent group did not show significant increase throughout 12 weeks (620/μl at week 2, P = 0.57). Changes in lymphocyte number following MTX withdrawal clearly distinguished the regressive LPD from the persistent LPD. Conclusion. A significant decrease in lymphocyte count at the LPD diagnosis and its restoration after MTX withdrawal were markedly associated with spontaneous regression of LPD developing during MTX treatment.

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EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update

竹内勤

Annals of the Rheumatic Diseases （Annals of the Rheumatic Diseases） 76 （ 6 ） 960 - 977 2017年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

Recent insights in rheumatoid arthritis (RA) necessitated updating the European League Against Rheumatism (EULAR) RA management recommendations. A large international Task Force based decisions on evidence from 3 systematic literature reviews, developing 4 overarching principles and 12 recommendations (vs 3 and 14, respectively, in 2013). The recommendations address conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GC); biological (b) DMARDs (tumour necrosis factor (TNF)-inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, clazakizumab, sarilumab and sirukumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (Janus kinase (Jak) inhibitors tofacitinib, baricitinib). Monotherapy, combination therapy, treatment strategies (treat-to-target) and the targets of sustained clinical remission (as defined by the American College of Rheumatology-(ACR)-EULAR Boolean or index criteria) or low disease activity are discussed. Cost aspects were taken into consideration. As first strategy, the Task Force recommends MTX (rapid escalation to 25 mg/week) plus short-term GC, aiming at >50% improvement within 3 and target attainment within 6 months. If this fails stratification is recommended. Without unfavourable prognostic markers, switching to-or adding-another csDMARDs (plus short-term GC) is suggested. In the presence of unfavourable prognostic markers (autoantibodies, high disease activity, early erosions, failure of 2 csDMARDs), any bDMARD (current practice) or Jak-inhibitor should be added to the csDMARD. If this fails, any other bDMARD or tsDMARD is recommended. If a patient is in sustained remission, bDMARDs can be tapered. For each recommendation, levels of evidence and Task Force agreement are provided, both mostly very high. These recommendations intend informing rheumatologists, patients, national rheumatology societies, hospital officials, social security agencies and regulators about EULAR's most recent consensus on the management of RA, aimed at attaining best outcomes with current therapies.

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Multiomic disease signatures converge to cytotoxic CD8 T cells in primary Sjögren's syndrome

Tasaki S., Suzuki K., Nishikawa A., Kassai Y., Takiguchi M., Kurisu R., Okuzono Y., Miyazaki T., Takeshita M., Yoshimoto K., Yasuoka H., Yamaoka K., Ikeura K., Tsunoda K., Morita R., Yoshimura A., Toyoshiba H., Takeuchi T.

Annals of the Rheumatic Diseases （Annals of the Rheumatic Diseases） 76 （ 8 ） 1458 - 1466 2017年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted. Objectives Multiomics study was conducted to elucidate the crucial molecular mechanisms of primary Sjögren's syndrome (SS) pathology. Methods We generated multiple data set from well-defined patients with SS, which includes whole-blood transcriptomes, serum proteomes and peripheral immunophenotyping. Based on our newly generated data, we performed an extensive bioinformatic investigation. Results Our integrative analysis identified SS gene signatures (SGS) dysregulated in widespread omics layers, including epigenomes, mRNAs and proteins. SGS predominantly involved the interferon signature and ADAMs substrates. Besides, SGS was significantly overlapped with SS-causing genes indicated by a genome-wide association study and expression trait loci analyses. Combining the molecular signatures with immunophenotypic profiles revealed that cytotoxic CD8 T cellswere associated with SGS. Further, we observed the activation of SGS in cytotoxic CD8 T cells isolated from patients with SS. Conclusions Our multiomics investigation identified gene signatures deeply associated with SS pathology and showed the involvement of cytotoxic CD8 T cells. These integrative relations across multiple layers will facilitate our understanding of SS at the system level.

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Importance of obtaining remission for work productivity and activity of patients with rheumatoid arthritis

竹内勤

Journal of Rheumatology （Journal of Rheumatology） 44 （ 8 ） 1112 - 1117 2017年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315162X

© The Journal of Rheumatology 2017. Objective. To identify the factors relevant to work and activity impairment in patients with rheumatoid arthritis. Methods. In total, 1274 consecutive patients were included. Work and activity impairment were measured by the Work Productivity and Activity Impairment questionnaire, and related clinical factors were examined. Results. Work and activity impairment was reported by 67.4% of the patients. Multivariable linear regression analyses revealed pain and non-remission to be associated with activity impairment and presenteeism. Patients in remission had significantly less activity impairment and presenteeism than those with low disease activity. Conclusion. Remission achievement is essential for ensuring work performance and activity.

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