研究者詳細 - 竹内　勤

論文 - 竹内　勤

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Sirukumab in rheumatoid arthritis refractory to sulfasalazine or methotrexate

Takeuchi Tsutomu, Yamanaka Hisashi, Harigai Masayoshi, Tamamura Ryo, Kato Yuichi, Ukyo Yoshifumi, Nakano Toshikazu, Hsu Benjamin, Tanaka Yoshiya

Arthritis Research and Therapy 20 42 2018年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1478-6354

Background: Sirukumab, a high-affinity human monoclonal antibody that selectively binds to interleukin-6, has demonstrated efficacy in the treatment of rheumatoid arthritis (RA) in global phase 1 and phase 2 studies. The present study evaluated the safety and efficacy of sirukumab, as monotherapy in Japanese patients with RA refractory to methotrexate or sulfasalazine. Methods: In this phase 3, double-blind study, 122 patients (age ≥ 20 years) were randomized (1:1, 61 patients in each arm) to sirukumab administered subcutaneously: 50 mg once every 4 weeks (q4w) or 100 mg once every 2 weeks (q2w) through 52 weeks. Disease-modifying anti-rheumatic drugs were allowed after 24 weeks. Safety was assessed and efficacy was evaluated using American College of Rheumatology (ACR) responses, Disease Activity Score C-reactive protein (DAS28-CRP) and Health Assessment Questionnaire-Disability Index (HAQ-DI). Results: Amongst the 122 randomized patients, 99 (81.1%) patients completed the study. Adverse events (AEs) were reported in 114/122 (93.4%) patients and serious AEs were reported in 9/122 (7.4%) patients. No deaths, major cardiovascular AEs, serious gastrointestinal perforations or tuberculosis cases were reported during this study period. Grade 3 hematologic abnormalities (neutropenia and leukopenia) were reported in seven patients and no grade 4 abnormalities were observed. ACR20 responses were observed within 2 weeks, achieved in 47/61 (77.0%, 50 mg q4w) patients and 44/61 (72.1%, 100 mg q2w) patients at week 16 and maintained through week 52. ACR50/70, DAS28-CRP and HAQ-DI responses were also maintained through week 52 in both groups. Conclusions: Safety findings were comparable between the two treatment groups. The 52-week administration of sirukumab at 50 mg q4w and 100 mg q2w was generally tolerable and with measurable efficacy in Japanese patients with RA refractory to methotrexate and sulfasalazine.

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Sirukumab in rheumatoid arthritis refractory to sulfasalazine or methotrexate: A randomized phase 3 safety and efficacy study in Japanese patients

Takeuchi T., Yamanaka H., Harigai M., Tamamura R., Kato Y., Ukyo Y., Nakano T., Hsu B., Tanaka Y.

Arthritis Research and Therapy （Arthritis Research and Therapy） 20 （ 1 ） 42 2018年03月

研究論文（学術雑誌）, 査読有り, ISSN 14786354

© 2018 The Author(s). Background: Sirukumab, a high-affinity human monoclonal antibody that selectively binds to interleukin-6, has demonstrated efficacy in the treatment of rheumatoid arthritis (RA) in global phase 1 and phase 2 studies. The present study evaluated the safety and efficacy of sirukumab, as monotherapy in Japanese patients with RA refractory to methotrexate or sulfasalazine. Methods: In this phase 3, double-blind study, 122 patients (age ≥ 20 years) were randomized (1:1, 61 patients in each arm) to sirukumab administered subcutaneously: 50 mg once every 4 weeks (q4w) or 100 mg once every 2 weeks (q2w) through 52 weeks. Disease-modifying anti-rheumatic drugs were allowed after 24 weeks. Safety was assessed and efficacy was evaluated using American College of Rheumatology (ACR) responses, Disease Activity Score C-reactive protein (DAS28-CRP) and Health Assessment Questionnaire-Disability Index (HAQ-DI). Results: Amongst the 122 randomized patients, 99 (81.1%) patients completed the study. Adverse events (AEs) were reported in 114/122 (93.4%) patients and serious AEs were reported in 9/122 (7.4%) patients. No deaths, major cardiovascular AEs, serious gastrointestinal perforations or tuberculosis cases were reported during this study period. Grade 3 hematologic abnormalities (neutropenia and leukopenia) were reported in seven patients and no grade 4 abnormalities were observed. ACR20 responses were observed within 2 weeks, achieved in 47/61 (77.0%, 50 mg q4w) patients and 44/61 (72.1%, 100 mg q2w) patients at week 16 and maintained through week 52. ACR50/70, DAS28-CRP and HAQ-DI responses were also maintained through week 52 in both groups. Conclusions: Safety findings were comparable between the two treatment groups. The 52-week administration of sirukumab at 50 mg q4w and 100 mg q2w was generally tolerable and with measurable efficacy in Japanese patients with RA refractory to methotrexate and sulfasalazine.

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Secukinumab after anti-tumour necrosis factor-α therapy

Dokoupilová E., Aelion J., Takeuchi T., Malavolta N., Sfikakis P., Wang Y., Rohrer S., Richards H.

Scandinavian Journal of Rheumatology 47 276 - 281 2018年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0300-9742

Objective: To assess the efficacy and safety of secukinumab in patients with rheumatoid arthritis (RA) who failed to respond to tumour necrosis factor- α (TNF-α) inhibitors. Method: This phase III double-blind, double-dummy, placebo-controlled study (NCT01770379) randomized (1:1:1) patients to subcutaneous secukinumab 150 mg, secukinumab 75 mg, or placebo at baseline, weeks 1, 2, 3, and 4, and then every 4 weeks. American College of Rheumatology (ACR) 20 response at week 24 was the primary endpoint. Secondary outcomes included the 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP), Health Assessment Questionnaire Disability Index (HAQ-DI), and ACR50 at week 24. Long-term treatment was planned for 5 years. Results: ACR20 response rates at week 24 for the secukinumab 150 mg and 75 mg groups were not statistically superior to placebo. None of the secondary endpoints was met for either secukinumab dose. Although not statistically significant, compared with placebo, numerically greater differences in least squares mean changes from baseline in HAQ-DI score and numerically higher ACR50 response rates were observed at week 24 in both secukinumab treatment groups. No new or unexpected adverse events were observed in this study compared with the large secukinumab safety database across psoriasis, psoriatic arthritis, ankylosing spondylitis, and other RA studies. Conclusions: Given that other second-line therapies have demonstrated efficacy in RA patients who failed to respond to TNF-α inhibitors, these findings may suggest that interleukin-17A inhibition with secukinumab does not provide additional benefit to these patients. This study further confirms the well-characterized safety profile of secukinumab.

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Inflammatory tenosynovitis and enthesitis induced by immune checkpoint inhibitor treatment

Inamo J., Kaneko Y., Takeuchi T.

Clinical Rheumatology （Clinical Rheumatology） 37 （ 4 ） 1 - 4 2018年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0770-3198

© 2018, International League of Associations for Rheumatology (ILAR). Reports about immune-related adverse events (IrAEs) induced by immune checkpoint inhibitors (ICIs) have been increasing. Although the importance of understanding joint involvement and myalgia as an IrAE has grown, little is known about its characteristics. The aim of this study was to investigate the incidence and clinical characteristics of articular IrAEs. We reviewed 133 patients who were treated with ICIs in our institution and referred to our rheumatologic. Among them, 2 (1.5%) developed arthritis during the use of anti-PD-1 inhibitor, and there was one patient with joint pain after anti-PD-L1 inhibitor who was referred to our department from another institution. No patients had antecedent inflammatory arthritis or any relevant medical history. All 3 patients were negative for anti-nuclear antibody, rheumatoid factor, and anti-cyclic citrullinated peptide antibody. The ultrasonography showed tenosynovitis and enthesitis in both small and large joints with no or insignificant synovitis. Joint pain improved gradually within 6 months with only NSAIDs in 2 patients, and disappeared quickly in the other patient 2 weeks after 20 mg/day of predonisolone. Our report suggested diverse phenotypes of joint involvement and highlighted the importance of accumulating such patients.

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Microscopic polyangiitis diagnosed by muscle specimen: a case report and literature review

竹内勤

Modern Rheumatology 2018年02月

研究論文（学術雑誌）, 共著, 査読有り

Clinical practice guideline for Sjogren’s syndrome 2017

竹内勤

Modern Rheumatology 2018年02月

研究論文（学術雑誌）, 共著, 査読有り

Follicular helper T cells in the pathogenesis of IgG4-related disease

Akiyama Mitsuhiro, Suzuki Katsuya, Yasuoka Hidekata, Kaneko Yuko, Yamaoka Kunihiro, Takeuchi Tsutomu

Rheumatology (United Kingdom) 57 （ 2 ） 236 - 245 2018年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1462-0324

IgG4-related disease (IgG4-RD) is a recently recognized disease entity characterized by high serum IgG4 concentrations and infiltration of IgG4⁺ plasma cells with hyperplastic ectopic germinal centres at affected sites. Although the underlying immune mechanism of this disease remains unclear, T cells are abundantly present at affected sites and key players in IgG4-RD pathogenesis. The role of T cell subsets has been investigated thoroughly in this disease. Recent advances in this field have clarified the importance of T follicular helper cells. In this review, we describe the role of T follicular helper cells in the disease process of IgG4-RD, in particular, for IgG4 class-switching, plasmablast and plasma cell differentiation, and germinal centre formation.

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Consensus-based recommendations for the use of biosimilars to treat rheumatological diseases

Kay J., Schoels M., Dörner T., Emery P., Kvien T., Smolen J., Breedveld F., Bijlsma J., Braun J., Bykerk V., Danese S., De Wit M., Goncalves J., Huizinga T., Isaacs J., Kavanaugh A., Kurki P., Luger T., Müller-Ladner U., Pavelkam K., Schellekens H., Strangfeld A., Takeuchi T., Voshaar M., Weisman M.

Annals of the Rheumatic Diseases （Annals of the Rheumatic Diseases） 77 （ 2 ） 165 - 174 2018年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

© 2018 Article author(s). The study aimed to develop evidence-based recommendations regarding the evaluation and use of biosimilars to treat rheumatological diseases. The task force comprised an expert group of specialists in rheumatology, dermatology and gastroenterology, and pharmacologists, patients and a regulator from ten countries. Four key topics regarding biosimilars were identified through a process of discussion and consensus. Using a Delphi process, specific questions were then formulated to guide a systematic literature review. Relevant English-language publications through November 2016 were searched systematically for each topic using Medline; selected papers and pertinent reviews were examined for additional relevant references; and abstracts presented at the 2015 and 2016 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) annual scientific meetings were searched for those about biosimilars. The experts used evidence obtained from these studies to develop a set of overarching principles and consensus recommendations. The level of evidence and grade of recommendation were determined for each. By the search strategy, 490 references were identified. Of these, 29 full-text papers were included in the systematic review. Additionally, 20 abstracts were retrieved from the ACR and EULAR conference abstract databases. Five overarching principles and eight consensus recommendations were generated, encompassing considerations regarding clinical trials, immunogenicity, extrapolation of indications, switching between bio-originators and biosimilars and among biosimilars, and cost. The level of evidence and grade of recommendation for each varied according to available published evidence. Five overarching principles and eight consensus recommendations regarding the evaluation and use of biosimilars to treat rheumatological diseases were developed using research-based evidence and expert opinion.

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Determinants of Patient’s Global Assessment of Disease Activity and Physician’s Global Assessment of Disease Activity in patients with rheumatoid arthritis

Kaneko Yuko, Takeuchi Tsutomu, Cai Zhihong, Sato Masayo, Awakura Kenta, Gaich Carol, Zhu Baojin, Guo Jiaying, Tanaka Yoshiya

Modern Rheumatology 1 - 8 2018年02月

研究論文（学術雑誌）, 共著, ISSN 1439-7595

Objectives: To assess the determinants of Patient’s Global Assessment of Disease Activity (PtGA) and Physician’s Global Assessment of Disease Activity (PhGA) in overall and Japanese patients with rheumatoid arthritis (RA) from two large randomized controlled trials. Methods: Post hoc analysis of overall and Japanese RA patients who had previous inadequate responses to methotrexate or who had no/minimal previous disease-modifying antirheumatic drug treatment. We examined correlations between PtGA/PhGA and tender joint count in 28 joints (TJC28), swollen joint count in 28 joints (SJC28), inflammatory markers, pain visual analog scale (VAS), and other patient-reported outcomes at baseline, Week 12, and Week 24. Determinants of PtGA/PhGA were identified. Results: In overall populations, pain VAS was the main determinant of PtGA, whereas TJC28 was the main determinant of PhGA in both studies. In Japanese populations, consistent with overall populations, pain VAS was the main determinant of PtGA in both studies; in contrast to overall populations, pain VAS and SJC28/TJC28 played an important role in PhGA. Conclusion: Pain was the most important determinant of PtGA, whereas determinants of PhGA varied between populations/studies and were mostly explained by pain/joint counts. Physicians should be aware of patients’ perceptions of disease activity when performing assessments/prescribing treatments.

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Follicular helper T cells in the pathogensis of IgG4-related disease

竹内勤

Rheumatology (Oxford) 57 236 - 245 2018年02月

研究論文（学術雑誌）, 共著, 査読有り

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Increased proportion of a CD38 high IgD + B cell subset in peripheral blood is associated with clinical and immunological features in patients with primary Sjögren's syndrome

竹内勤

Clinical Immunology （Clinical Immunology） 187 85 - 91 2018年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 15216616

© 2017 Elsevier Inc. We investigated the correlation between the increased proportion of peripheral B cell subsets and clinical and immunological features in primary Sjögren's syndrome (pSS). We found that the proportion of CD19 + B cells was significantly increased in pSS as compared with HC and was correlated with serum IgG levels. Moreover, in vitro IgG production by CD19 + B cells was significantly increased in pSS and was positively and significantly correlated with serum IgG levels. FACS analysis revealed that the proportions of peripherally CD38 high IgD + B cells and CD38 high IgD − B cells were significantly increased in pSS. In addition, the proportion of CD38 high IgD + B cells positively correlated with ESSDAI scores and serum levels of IgG, anti-Ro/SSA and anti-La/SSB antibodies while that of CD38 high IgD − B cells showed no correlation with these parameters. Our data suggest that increased proportion of CD38 high IgD + B cells in pSS is involved in IgG overproduction including autoantibodies, and correlates with disease progression.

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Increased circulating CD14brightCD16+ intermediate monocytes are regulated by TNF-α and IL-6 axis in accordance with disease activity in patients with rheumatoid arthritis

竹内勤

Clinical and experimental rheumatology （Clinical and experimental rheumatology） 36 （ 4 ） 540 - 544 2018年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0392856X

OBJECTIVES: Although circulating CD14brightCD16+ monocyte subsets are increased in inflammatory disease, the pathogenesis of the increase in the inflammatory condition of the cells is still unclear and the relationship to cytokines is unknown particularly in rheumatoid arthritis (RA). The purpose of this study was to investigate the influence anti-cytokine treatment has on CD14brightCD16+ monocytes in patients with RA.METHODS: Thirty-two RA patients and 14 healthy volunteers (HV) were enrolled in this study. All the patients had never been treated with methotrexate (MTX) or biological agents. Peripheral blood samples and clinical information of the patients were obtained at the time of 0, 12 and 24 weeks of treatment. Peripheral blood samples were also obtained from the HV. The expression levels of CD14 and CD16 on monocytes were measured by flow cytometry (FCM).RESULTS: Eight patients received anti-interleukin (IL)-6 receptor antibody, tocilizumab (TCZ) treatment alone, 12 patients received anti-tumour necrosis factor (TNF)-α antibody, adalimumab (ADA) with MTX treatment and the others received only MTX treatment. FCM analysis revealed that the proportion of CD14brightCD16+ monocytes significantly increased in patients at baseline compared with HV. The proportion of CD14brightCD16+ monocytes significantly decreased after TCZ, and ADA with MTX treatment. The proportion of intermediate monocytes was significantly and positively correlated with disease activity and it improved in accordance with the proportion of CD14brightCD16+ monocytes after inhibition of signal transduction of inflammatory cytokines.CONCLUSIONS: We showed that the population of CD14brightCD16+ monocytes significantly decreased with the change of disease activity by key cytokines, IL-6 or TNF-α signal blockade in RA. This result indicates that the proportion of those monocytes is important for reflecting disease activity in RA.

RANKL: A therapeutic target for bone destruction in rheumatoid arthritis

Tanaka S., Tanaka Y., Ishiguro N., Yamanaka H., Takeuchi T.

Modern Rheumatology （Modern Rheumatology） 28 （ 1 ） 9 - 16 2018年01月

研究論文（学術雑誌）, 査読有り, ISSN 14397595

© 2017 Japan College of Rheumatology. Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by progressive joint destruction. Recent studies have indicated the critical involvement of osteoclasts in bone destruction in RA. The osteoclast differentiation factor receptor activator of NF-κB ligand (RANKL), which belongs to the tumor necrosis factor superfamily, plays a critical role in osteoclast differentiation and bone destruction in RA. Denosumab, an antibody against human RANKL, efficiently suppressed the progression of bone erosion in RA patients in randomized controlled studies, and is considered as a putative therapeutic option for preventing bone destruction in RA.

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

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

Clinical and Experimental Rheumatology （Clinical and Experimental Rheumatology） 36 （ 3 ） S157 - S164 2018年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0392-856X

© Copyright CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 2018. Objective. To identify biomarkers for disease activity in IgG4-related disease (IgG4-RD) and primary Sjögren's syndrome (pSS). Methods. Forty-three consecutive treatment- naïve patients with IgG4-RD, 62 patients with pSS, and 5 patients with sicca syndrome were enrolled. IgG4-RD and pSS disease activity was assessed based on the IgG4-RD responder index (IgG4-RD RI) and EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI), respectively. The associations of biomarkers with disease activity were examined. Results. Comparison of the three diseases identified the serum levels of IgG, IgG4, IgG4/IgG ratio, IgE, and soluble interleukin-2 receptor (sIL-2R) for IgG4-RD and the serum levels of IgM and sIL-2R and lymphocyte counts for pSS as potential biomarkers of disease activity. Among these, serum sIL-2R levels correlate with baseline IgG4-RD RI scores and the number of affected organs in IgG4-RD (p=0.74, p<0.0001 and p=0.75, p<0.0001, respectively). Serum sIL-2R levels also correlate with ESSDAI scores and the number of affected organs in pSS (P=0.67, p<0.0001 and p=0.41, p<0.0001, respectively). Receiver operating characteristic curve analysis suggested serum sIL-2R levels as an efficient biomarker to distinguish the presence of extra-dacryosialadenitis involvements in IgG4-RD with a cut-off value of 424 U/mL (AUC=0.93, p<0.0001), and in pSS with 452 U/mL (AUC=0.89, p<0.0001). Serum sIL-2R levels decreased significantly after treatment in patients with IgG4-RD and pSS. Conclusion. Serum sIL-2R levels are a potentially valuable biomarker for evaluating disease activity and treatment response in IgG4-RD and pSS.

Addendum

Takeuchi Tsutomu

Proceedings of the Japan Academy Series B: Physical and Biological Sciences 94 （ 1 ） 56 - 57 2018年01月

研究論文（学術雑誌）, 単著, 査読有り, ISSN 0386-2208

Molecules involved in the disease process facilitated our understanding of pathogenesis of the disease with unknown etiology such as immune-mediated and inflammatory diseases. Moreover, the targeted therapies against the proposed molecular targets by biological agents provide enormous benefits to the patients and societies. Here, I will review recent progress of the biological treatment in the immune-inflammatory diseases by focusing on the rheumatoid arthritis, the disease characterized by persistent polyarthritis leading to joint destruction and disability with autoimmune features, as a role model.

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Association Between Reappearance of Myeloperoxidase–Antineutrophil Cytoplasmic Antibody and Relapse in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

Watanabe Haruki, Sada Ken Ei, Matsumoto Yoshinori, Harigai Masayoshi, Amano Koichi, Dobashi Hiroaki, Fujimoto Shouichi, Usui Joichi, Yamagata Kunihiro, Atsumi Tatsuya, Banno Shogo, Sugihara Takahiko, Arimura Yoshihiro, Matsuo Seiichi, Makino Hirofumi, Sugiyama Hitoshi, Takasaki Yoshinari, Ishizu Akihiro, Fujii Takao, Okada Yasunori, Homma Sakae, Tsuboi Naotake, Kumagai Shunichi, Muso Eri, Murakawa Yohko, Hasegawa Hitoshi, Yumura Wako, Matsubara Hiroaki, Yoshida Masaharu, Katsuoka Kensei, Ogawa Noriyoshi, Komatsuda Atsushi, Ito Satoshi, Kawakami Atsushi, Nakaya Izaya, Saito Takao, Ito Takafumi, Hirawa Nobuhito, Yamamura Masahiro, Nakano Masaaki, Nitta Kosaku, Ogura Makoto, Naniwa Taio, Ozaki Shoichi, Hirahashi Junichi, Hosoya Tatsuo, Wada Takashi, Horikoshi Satoshi, Kawaguchi Yasushi, Takeuchi Tsutomu

Arthritis and Rheumatology 2018年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2326-5191

Objective: To evaluate clinical links between levels of myeloperoxidase (MPO)–antineutrophil cytoplasmic antibody (ANCA) and relapse in patients with ANCA-associated vasculitis (AAV) using a data set from 2 nationwide prospective cohort studies. Methods: From the cohort studies, MPO-ANCA–positive patients who achieved remission during the 6 months after remission induction therapy were enrolled. We measured MPO-ANCA levels at months 0, 3, 6, 12, 18, 24, and at the time of relapse. The primary outcome measure was relapse. A nested case–control analysis and multivariable analysis were performed to investigate the relationship between ANCA reappearance and relapse. Results: Of 271 patients, 183 were classified as having microscopic polyangiitis, 34 as having granulomatosis with polyangiitis, 15 as having eosinophilic granulomatosis with polyangiitis, and 39 were unclassifiable. The median age was 73 years, and 165 (61%) were female. In 195 patients (72%), MPO-ANCA levels decreased to normal levels within 6 months after commencement of treatment, and MPO-ANCA reappeared in 73 of 181 patients (40%) with complete follow-up data. Reappearance of MPO-ANCA was more frequent in patients with relapse than in 75 age- and sex-matched control patients without relapse (odds ratio 26.2 [95% confidence interval 8.2–101], P < 0.0001) after adjustment for confounding factors. Conclusion: Reappearance of MPO-ANCA could be a clinically useful biomarker for predicting relapse in patients with MPO-ANCA–positive AAV in remission. This suggests that routine MPO-ANCA monitoring should be implemented in this patient population.

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Effectiveness and safety of initiating adalimumab plus ≥12 mg/week methotrexate with adjustable dosing in biologic-naïve patients with early rheumatoid arthritis

Tanaka Yoshiya, Mimori Tsuneyo, Yamanaka Hisashi, Nakajima Ryo, Morita Kazuo, Kimura Junko, Takeuchi Tsutomu

Modern Rheumatology 2018年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objectives: This real-world study assessed the effectiveness and safety outcomes of initiating adalimumab and methotrexate (≥12 mg/week) with adjustable dosing in Japanese patients with early rheumatoid arthritis (RA). Methods: This single-arm, prospective postmarketing observational study (conducted from September 2012 to March 2017 at 119 sites) enrolled biologic-naïve patients with early RA (≤2 years duration) and a Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) >3.2 who were treated with methotrexate for ≥3 months and had initiated treatment with adalimumab and methotrexate (≥12 mg/week). This report presents 52-week data. The primary outcome was the proportion of patients who achieved DAS28-CRP scores <2.6 at week 52. Results: Overall, 293 of 346 enrolled patients were included in the effectiveness population: women, 73%; mean (standard deviation) age, 54.3 (13.9) years; DAS28-CRP score, 4.51 (0.90); and modified total Sharp score (mTSS), 7.69 (9.98). At week 52, 77% of patients achieved clinical remission (DAS28-CRP <2.6), 92.3% achieved low disease activity (DAS28-CRP ≤3.2), and 86% of evaluable patients experienced structural remission (ΔmTSS ≤0.5). Conclusion: Adalimumab plus methotrexate (≥12 mg/week) with adjustable dosing was well tolerated, and could be a beneficial treatment option for Japanese patients with early RA.

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Factors predicting the therapeutic response to methotrexate in Japanese patients with rheumatoid arthritis

Hakamata Jun, Kaneko Yuko, Shimizu Mikiko, Yamaoka Kunihiro, Maruyama Junya, Takeuchi Tsutomu, Mochizuki Mayumi, Hashiguchi Masayuki

Biological and Pharmaceutical Bulletin 41 （ 9 ） 1414 - 1422 2018年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0918-6158

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

Impact of subclinical synovitis in ankles and feet detected by ultrasonography in patients with rheumatoid arthritis

Inamo J., Kaneko Y., Sakata K., Takeuchi T.

International Journal of Rheumatic Diseases （International Journal of Rheumatic Diseases） 22 （ 1 ） 62 - 67 2018年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1756-1841

© 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd Objective: To investigate the impact of subclinical synovitis detected by ultrasonography (US) on the ankles and feet of patients with rheumatoid arthritis. Methods: We retrospectively reviewed the data of patients (n = 59) who underwent US. Results: The functional ability and quality of life (QoL) of patients in the subclinical group were impaired. While the physician visual analog scale (VAS) scores significantly decreased in the subclinical group, patient and pain VAS scores significantly decreased only in patients without synovitis. Conclusion: US-detected subclinical foot and ankle synovitis considerably affected patient functional status and QoL; however, it was often unnoticed by physicians.

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Persistent fever and destructive arthritis caused by dialysis-related amyloidosis

Matsumoto K., Kikuchi J., Kaneko Y., Yasuoka H., Suzuki K., Tokuyama H., Kameyama K., Yamaoka K., Takeuchi T.

Medicine (United States) （Medicine (United States)） 97 （ 1 ） e9359 2018年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0025-7974

Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc. Rationale: Dialysis-related amyloidosis (DRA) can present rheumatic manifestations in patients on long-term hemodialysis. Typical articular symptoms with DRA involve carpal-tunnel syndrome, effusion in large joints, spondyloarthropathy, or cystic bone lesions, which are usually with non-inflammatory processes. Patient concerns: A 64-year-old man on hemodialysis for >30 years was admitted because of intermittent fever, polyarthritis, and elevated serum C-reactive protein (CRP) level, which was continuous for 2 years. Several antibiotics were ineffective for 3 months before his admission. On physical examination, joint swelling was observed at bilateral wrists, knees, ankles, and hip joints. Laboratory tests revealed elevation of serum inflammatory markers and β2-microglobulin (β2-MG). Synovial fluid showed predominant infiltration of polymorphonuclear leukocytes and the increase of β2-MG level. Diagnosis: Significant deposition of β2-MG with inflammatory cell infiltration was found in biopsied samples from synovium, skin, and ileum. Interventions: We decided to switch to the hemodialysis column with membrane that can effectively absorb β2-MG in circulation. Outcomes: The relief of symptoms and a decrease of CRP level by changing the membrane lead to the final diagnosis of DRA. Lessons: Our case demonstrates that DRA arthropathy can be inflammatory and destructive, and also develop systemic inflammatory signs and symptoms. In such cases, aggressive absorption of β2-MG in circulation might help the amelioration of symptoms.

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