研究者詳細 - 竹内　勤

論文 - 竹内　勤

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Significant association between joint ultrasonographic parameters and synovial inflammatory factors in rheumatoid arthritis

Kondo Y., Suzuki K., Inoue Y., Sakata K., Takahashi C., Takeshita M., Kassai Y., Miyazaki T., Morita R., Niki Y., Kaneko Y., Yasuoka H., Yamaoka K., Yoshimura A., Takeuchi T.

Arthritis Research and Therapy （Arthritis Research and Therapy） 21 （ 1 ） 14 2019年10月

研究論文（学術雑誌）, 査読有り, ISSN 14786354

© 2019 The Author(s). Background: Ultrasonography (US) can directly demonstrate joint inflammation, including grayscale (GS) signs of synovial hypertrophy and power Doppler (PD) techniques to demonstrate increased blood flow and vascularization. Recently, echogenicity, especially hypoechoic synovium, has also been associated with local inflammatory activity. However, only a few studies have demonstrated correlation between histopathologic and immunopathologic evaluation and US findings. The aim of this study was to clarify whether joint US findings including synovial hypertrophy, vascularity, and echogenicity can accurately characterize synovial pathophysiology in patients with active rheumatoid arthritis (RA). Methods: A total of 44 patients with RA were included, both treated (n = 25) and untreated (n = 19) and scheduled for US examination of the knee joint with synovial fluid (SF) aspiration and two treated patients also underwent synovial biopsy. US images were quantitatively analyzed using grayscale assessment of synovial hypertrophy and PD for vascularity and echogenicity. Levels of nine SF cytokines and growth factors were also measured. Results: Both US synovial hypertrophy and PD vascularity significantly correlated with SF inflammatory cytokine levels such as IL-6, IL-8, IL-1β and IL-10 in untreated patients. Angiogenic factors, including vascular endothelial growth factor (VEGF), only correlated with PD vascularity. In the treated patients, the associations between synovial hypertrophy and any cytokines were diminished, although synovial vascularity and echogenicity correlated with IL-6 and VEGF (p < 0.05). Histopathologic analysis revealed that hypoechogenicity of the synovium correlated with marked infiltration of lymphocytes and hypervascularity. Conclusions: We demonstrated the pathophysiological origins of US findings in the joint. The degree of US vascularity of the synovium correlated with local inflammatory cytokine levels and angiogenetic factors in patients with active RA. Synovial echogenicity, and not hypertrophy, correlated with inflammation, especially in treated patients with RA.

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Effects of the anti-RANKL antibody denosumab on joint structural damage in patients with rheumatoid arthritis treated with conventional synthetic disease-modifying antirheumatic drugs (DESIRABLE study): a randomised, double-blind, placebo-controlled phase 3 trial.

Takeuchi T, Tanaka Y, Soen S, Yamanaka H, Yoneda T, Tanaka S, Nitta T, Okubo N, Genant HK, van der Heijde D

Annals of the rheumatic diseases 2019年04月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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Efficacy and safety of namilumab, a human monoclonal antibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) ligand in patients with rheumatoid arthritis (RA) with either an inadequate response to background methotrexate therapy or an inadequate response or intolerance to an anti-TNF (tumour necrosis factor) biologic therapy: a randomized, controlled trial

Taylor Peter C., Saurigny Didier, Vencovsky Jiri, Takeuchi Tsutomu, Nakamura Tadashi, Matsievskaia Galina, Hunt Barbara, Wagner Thomas, Souberbielle Bernard

ARTHRITIS RESEARCH & THERAPY 21 （ 1 ） 101 2019年04月

研究論文（学術雑誌）, 査読有り, ISSN 1478-6354

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Clinicopathological features of clinical methotrexate-related lymphoproliferative disorders.

Tokuhira M, Saito S, Suzuki K, Higashi M, Momose S, Shimizu T, Mori T, Kimura Y, Amano K, Okamoto S, Takeuchi T, Tamaru JI, Kizaki M

Leukemia & lymphoma 1 - 8 2019年04月

研究論文（学術雑誌）, 査読有り, ISSN 1042-8194

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Demographics and clinical characteristics associated with sustained remission and continuation of sustained remission in patients with rheumatoid arthritis treated with adalimumab

Kimura Noriko, Suzuki Katsuya, Takeuchi Tsutomu

INFLAMMATION AND REGENERATION 39 5 2019年03月

研究論文（学術雑誌）, 査読有り, ISSN 1880-8190

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Histopathological classification of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis in a nationwide Japanese prospective 2-year follow-up cohort study

Yamagata K., Usui J., Nagata M., Sugiyama H., Sada K., Muso E., Harigai M., Amano K., Atsumi T., Fujimoto S., Yuzawa Y., Kobayashi M., Saito T., Ito T., Hirawa N., Homma S., Dobashi H., Tsuboi N., Ishizu A., Arimura Y., Makino H., Matsuo S., Takasaki Y., Banno S., Sugihara T., Murakawa Y., Hasegawa H., Komatsuda A., Ito S., Fujii T., Kawakami A., Nakaya I., 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., Okada Y., Takeuchi T., Nakagawa N., Takeda S., Katabuchi R., Iwano M.

Clinical and Experimental Nephrology （Clinical and Experimental Nephrology） 23 （ 3 ） 387 - 394 2019年03月

研究論文（学術雑誌）, 査読有り, ISSN 13421751

© 2018, Japanese Society of Nephrology. Background: The prognostic value of the EUVAS-proposed histopathological classification of anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis has been evaluated throughout the world. Here, we performed a Japanese nationwide biopsy survey to assess the association between this histopathological classification and renal prognosis after 2-year follow-up in ANCA-associated glomerulonephritis. Methods: We collected 67 renal biopsy materials of the 321 entries in the RemIT-JAV-RPGN cohort study, and assessed their histologies. Based on the EUVAS-proposed histopathological classification and some histological parameters, we statistically evaluated renal survival and the comparison of renal function for 2 years. Results: Based on the histopathological classification, the largest number of biopsy samples belonged to the Focal class, followed by the Mixed, Crescentic, and Sclerotic classes (n = 30, 19, 10, 8, respectively). Although the number of events might be too low (four patients with renal death) to make this conclusion, the Focal and Mixed classes had higher renal-survival rates compared to the others in the renal-survival curve. Comparing renal function among all classes, the estimated glomerular filtration rate (eGFR) throughout 2-year follow-up period was significantly higher in the Focal class compared to the other 3 classes. The eGFR-values in the Crescentic, Mixed, and Sclerotic classes increased with time. Based on both combined results, the Focal class could be the best prognosis. Conclusion: This histopathological classification was valuable for both the stratification of renal function and the estimation of partial renal survival during 2-year follow-up in ANCA-associated glomerulonephritis.

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Radiographic and clinical outcomes following etanercept monotherapy in Japanese methotrexate-naïve patients with active rheumatoid arthritis.

Takeuchi T, Miyasaka N, Pedersen R, Sugiyama N, Hirose T

Modern rheumatology 1 - 10 2019年03月

研究論文（学術雑誌）, 査読有り, ISSN 1439-7595

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Efficacy and safety of sirukumab in Japanese patients with active rheumatoid arthritis who were refractory or intolerant to anti-tumor necrosis factor therapy: Subgroup analysis of a randomized, double-blind, multicenter, phase 3 study (SIRROUND-T)

Tanaka Y., Takeuchi T., Harigai M., Yamanaka H., Nakano T., Akagi K., Ukyo Y., Hsu B.

Modern Rheumatology （Modern Rheumatology） 29 （ 2 ） 306 - 313 2019年03月

研究論文（学術雑誌）, 査読有り, ISSN 14397595

© 2018, © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Objective: To evaluate the efficacy and safety of sirukumab, a human anti-interleukin six monoclonal antibody, in Japanese patients with rheumatoid arthritis who were refractory to anti-tumor necrosis factor therapy. Methods: This subgroup analysis, based on a double-blind, placebo-controlled, 52-week phase 3, global study (SIRROUND-T) assessed the American College of Rheumatology (ACR) 20 response at week 16 (primary endpoint). Secondary endpoints: ACR 50, Disease Activity Score in 28 joints-C reactive protein, Health Assessment Questionnaire-Disability Index and safety were assessed. Results 116/878 patients received sirukumab 50 mg/4 weeks (q4w, n = 35), 100 mg/2 weeks (q2w, n = 44) or placebo (n = 37) subcutaneously. Significantly more patients achieved ACR 20 response at week 16 with sirukumab (50 mg q4w:20 [57.1%]; p <.001, 100 mg q2w:24 [54.5%]; p =.001) versus placebo (7 [18.9%]); consistent significant improvement in secondary endpoints at week 24 and 52 was observed. At week 24, incidence of treatment-emergent adverse events (TEAEs) was numerically higher with sirukumab groups (50 mg q4w:29 [82.9%]; 100 mg q2w:38 [86.4%] versus placebo (28 [75.7%]); however, at week 52, sirukumab combined groups had comparable incidence of TEAEs. Conclusion: Efficacy findings through 52 weeks were comparable between sirukumab doses in Japanese patients and consistent with primary SIRROUND-T study results. No new safety signals were observed.

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Pulmonary Vein Vasculitis Presenting as Multiple Pulmonary Nodules in a Patient with Systemic Lupus Erythematosus

Tamai Hiroya, Nishina Naoshi, Takeuchi Tsutomu

JOURNAL OF RHEUMATOLOGY 46 （ 3 ） 323 - 324 2019年03月

研究論文（学術雑誌）, 査読有り, ISSN 0315-162X

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Development of the Asia Pacific Lupus Collaboration cohort

Kandane-Rathnayake R., Golder V., Louthrenoo W., Luo S., Jan Wu Y., Li Z., An Y., Lateef A., Sockalingam S., Navarra S., Zamora L., Hamijoyo L., Katsumata Y., Harigai M., Chan M., O’Neill S., Goldblatt F., Hao Y., Zhang Z., Al-Saleh J., Khamashta M., Takeuchi T., Tanaka Y., Bae S., Lau C., Hoi A., Nikpour M., Morand E.

International Journal of Rheumatic Diseases （International Journal of Rheumatic Diseases） 22 （ 3 ） 425 - 433 2019年03月

研究論文（学術雑誌）, 査読有り, ISSN 17561841

© 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd Aim: The aim of this manuscript is to describe the development of the Asia Pacific Lupus Collaboration (APLC) cohort. Method: The APLC cohort is an ongoing, prospective longitudinal cohort. Adult patients who meet either the American College of Rheumatology (ACR) Modified Classification Criteria for systemic lupus erythematosus (SLE), or the Systemic Lupus International Collaborating Clinics (SLICC) Classification Criteria, and provide informed consent are recruited into the cohort. Patients are routinely followed up at 3- to 6-monthly intervals. Information on demographics, clinical manifestations, treatment, pathology results, outcomes, and patient-reported quality of life (Short-form 36 version 2) are collected using a standardized case report form. Each site is responsible for obtaining local ethics and governance approval, patient recruitment, data collection, and data transfer into a centralized APLC database. Results: The latest APLC cohort comprises 2160 patients with >12 000 visits from Australia, China, Hong Kong, Indonesia, Japan, Malaysia, Philippines, Singapore, Taiwan and Thailand. The APLC has proposed the Lupus Low Disease Activity State (LLDAS) as a treat-to-target (T2T) endpoint, and reported several retrospective and cross-sectional analyses consistent with the validity of LLDAS. Longitudinal validation of LLDAS as a T2T endpoint is currently underway. Conclusion: The APLC cohort is one of the largest contemporary SLE patient cohorts in the world. It is the only cohort with substantial representation of Asian patients. This cohort represents a unique resource for future clinical research including evaluation of other endpoints and quality of care.

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Safety and tolerability of anifrolumab, a monoclonal antibody targeting type I interferon receptor, in Japanese patients with systemic lupus erythematosus: A multicenter, phase 2, open-label study.

Tanaka Y, Takeuchi T, Okada M, Ishii T, Nakajima H, Kawai S, Nagashima T, Hayashi N, Wang L, Tummala R

Modern rheumatology 1 - 8 2019年02月

研究論文（学術雑誌）, 査読有り, ISSN 1439-7595

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Does microbiome contribute to HLA-B52-positive Takayasu arteritis?

Akiyama M, Kaneko Y, Takeuchi T

Modern rheumatology 1 - 5 2019年02月

研究論文（学術雑誌）, 査読有り, ISSN 1439-7595

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Safety and tolerability of sifalimumab, an anti-interferon-α monoclonal antibody, in Japanese patients with systemic lupus erythematosus: A multicenter, phase 2, open-label study.

Takeuchi T, Tanaka Y, Matsumura R, Saito K, Yoshimura M, Amano K, Atsumi T, Suematsu E, Hayashi N, Wang L, Tummala R

Modern rheumatology 1 - 8 2019年02月

研究論文（学術雑誌）, 査読有り, ISSN 1439-7595

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Safety profile of baricitinib in Japanese patients with active rheumatoid arthritis with over 1.6 years median time in treatment: An integrated analysis of Phases 2 and 3 trials.

Harigai M, Takeuchi T, Smolen JS, Winthrop KL, Nishikawa A, Rooney TP, Saifan CG, Issa M, Isaka Y, Akashi N, Ishii T, Tanaka Y

Modern rheumatology 1 - 8 2019年02月

研究論文（学術雑誌）, 査読有り, ISSN 1439-7595

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Dose reduction of baricitinib in patients with rheumatoid arthritis achieving sustained disease control: Results of a prospective study

Takeuchi T., Genovese M., Haraoui B., Li Z., Xie L., Klar R., Pinto-Correia A., Otawa S., Lopez-Romero P., De La Torre I., Macias W., Rooney T., Smolen J.

Annals of the Rheumatic Diseases （Annals of the Rheumatic Diseases） 78 （ 2 ） 171 - 178 2019年02月

研究論文（学術雑誌）, 査読有り, ISSN 00034967

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. Objectives This study investigated the effects of dose step-down in patients with rheumatoid arthritis (RA) who achieved sustained disease control with baricitinib 4 mg once a day. Methods Patients who completed a baricitinib phase 3 study could enter a long-term extension (LTE). In the LTE, patients who received baricitinib 4 mg for ≥15 months and maintained CDAI low disease activity (LDA) or remission (REM) were blindly randomised to continue 4 mg or taper to 2 mg. Patients could rescue (to 4 mg) if needed. Efficacy and safety were assessed through 48 weeks. Results Patients in both groups maintained LDA (80% 4 mg; 67% 2 mg) or REM (40% 4 mg; 33% 2 mg) over 48 weeks. However, dose reduction resulted in small, statistically significant increases in disease activity at 12, 24 and 48 weeks. Dose reduction also produced earlier and more frequent relapse (loss of step-down criteria) over 48 weeks compared with 4 mg maintenance (23% 4 mg vs 37% 2 mg, p=0.001). Rescue rates were 10% for baricitinib 4 mg and 18% for baricitinib 2 mg. Dose reduction was associated with a numerically lower rate of non-serious infections (30.6 for baricitinib 4 mg vs 24.9 for 2 mg). Rates of serious adverse events and adverse events leading to discontinuation were similar across groups. Conclusions In a large randomised, blinded phase 3 study, maintenance of RA control following induction of sustained LDA/REM with baricitinib 4 mg was greater with continued 4 mg than after taper to 2 mg. Nonetheless, most patients tapered to 2 mg could maintain LDA/REM or recapture with return to 4 mg if needed.

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Dose reduction of baricitinib in patients with rheumatoid arthritis achieving sustained disease control: results of a prospective study

Takeuchi Tsutomu, Genovese Mark C., Haraoui Boulos, Li Zhanguo, Xie Li, Klar Rena, Pinto-Correia Ana, Otawa Susan, Lopez-Romero Pedro, de la Torre Inmaculada, Macias William, Rooney Terence P., Smolen Josef S.

ANNALS OF THE RHEUMATIC DISEASES 78 （ 2 ） 171 - 178 2019年02月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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Dose reduction of baricitinib in patients with rheumatoid arthritis achieving sustained disease control: results of a prospective study.

Takeuchi T, Genovese MC, Haraoui B, Li Z, Xie L, Klar R, Pinto-Correia A, Otawa S, Lopez-Romero P, de la Torre I, Macias W, Rooney TP, Smolen JS

Annals of the rheumatic diseases 78 （ 2 ） 171 - 178 2019年02月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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Cardiovascular Safety During Treatment with Baricitinib in Rheumatoid Arthritis.

Taylor PC, Weinblatt ME, Burmester GR, Rooney TP, Witt S, Walls CD, Issa M, Salinas CA, Saifan C, Zhang X, Cardoso A, González-Gay MA, Takeuchi T

Arthritis & rheumatology (Hoboken, N.J.) 2019年01月

研究論文（学術雑誌）, 査読有り, ISSN 2326-5191

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Efficacy and safety of tofacitinib in Japanese patients with rheumatoid arthritis by background methotrexate dose: A post hoc analysis of clinical trial data.

Takeuchi T, Yamanaka H, Yamaoka K, Arai S, Toyoizumi S, DeMasi R, Fukuma Y, Hirose T, Sugiyama N, Zwillich SH, Tanaka Y

Modern rheumatology 1 - 11 2019年01月

研究論文（学術雑誌）, 査読有り, ISSN 1439-7595

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Usefulness of serum Krebs von den Lungen-6 for the management of myositis-associated interstitial lung disease.

Takanashi S, Nishina N, Nakazawa M, Kaneko Y, Takeuchi T

Rheumatology (Oxford, England) 2019年01月

研究論文（学術雑誌）, 査読有り, ISSN 1462-0324

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Efficacy of denosumab with regard to bone destruction in prognostic subgroups of Japanese rheumatoid arthritis patients from the phase II DRIVE study.

Ishiguro N, Tanaka Y, Yamanaka H, Yoneda T, Ohira T, Okubo N, Genant HK, van der Heijde D, Takeuchi T

Rheumatology (Oxford, England) 2019年01月

研究論文（学術雑誌）, 査読有り, ISSN 1462-0324

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Safety Profile of Baricitinib in Patients with Active Rheumatoid Arthritis with over 2 Years Median Time in Treatment

Smolen Josef S., Genovese Mark C., Takeuchi Tsutomu, Hyslop David L., Macias William L., Rooney Terence, Chen Lei, Dickson Christina L., Camp Jennifer Riddle, Cardillo Tracy E., Ishii Taeko, Winthrop Kevin L.

JOURNAL OF RHEUMATOLOGY 46 （ 1 ） 7 - 18 2019年01月

研究論文（学術雑誌）, 査読有り, ISSN 0315-162X

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Initial presentation determines clinical entity in patients with anti-centromere antibody positivity

Tsukamoto M., Suzuki K., Takeuchi T.

International Journal of Rheumatic Diseases （International Journal of Rheumatic Diseases） 22 （ 1 ） 103 - 107 2019年01月

研究論文（学術雑誌）, 査読有り, ISSN 17561841

© 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd Aim: Anti-centromere antibody (ACA) is often detected in patients with autoimmune diseases, including limited cutaneous systemic sclerosis (SSc), Sjögren's syndrome (SS), and primary biliary cholangitis (PBC). The association between autoimmune disease and ACA positivity remains unclear. We sought to clarify the clinical features of ACA-positive patients and their association with autoantibodies. Method: A total of 309 cases of a discrete-speckled pattern anti-nuclear antibody (ANA) test and/or positive ACA who visited our department were retrospectively enrolled. Clinical and immunological data were collected and statistically analyzed. Result: A proportion of second and/or third ANA patterns were speckled (16%), homogenous (7%), cytoplasmic (3%) and/or nucleolar (3%). Of the 309 patients, 186 had Raynaud's phenomenon, 149 had sclerodactyly, and 162 had oral and/or ocular dryness. A total of 214 patients were classified into 17 autoimmune diseases based on their symptoms at the initial visit, while the other 95 patients did not meet any criteria. Most of the 214 patients were diagnosed with SSc and/or SS; 25 and 22 additional patients were diagnosed with rheumatoid arthritis and PBC, respectively. Higher titers of immunoglobulins were observed in patients diagnosed with autoimmune disease compared to patients without a diagnosis. The mean observation period was 80 months. Three additional patients received interim diagnoses based on new symptoms or organ involvement. In the other patients, the diagnosis made at the first visit was not changed over the observation period. Conclusion: Our study confirmed that many ACA-positive cases can be classified into an autoimmune disease type on presentation.

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Ten-year observation of patients with primary Sjögren's syndrome: Initial presenting characteristics and the associated outcomes.

Tsukamoto M, Suzuki K, Takeuchi T

International journal of rheumatic diseases 2018年12月

研究論文（学術雑誌）, 査読有り, ISSN 1756-1841

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Response to: 'Some concerns from Turkey' by Bilgin et al.

Kaneko Y, Kameda H, Ikeda K, Ishii T, Murakami K, Takamatsu H, Tanaka Y, Abe T, Takeuchi T

Annals of the rheumatic diseases 2018年12月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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Tocilizumab in patients with adult-onset still's disease refractory to glucocorticoid treatment

Kaneko Yuko, Kameda Hideto, Ikeda Kei, Ishii Tomonoti, Murakami Kosaku, Takamatsu Hyota, Tanaka Yoshiya, Abe Takayuki, Takeuchi Tsutomu

Annals of the rheumatic diseases 77 1270 - 1279 2018年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

Objective: To evaluate the efficacy and safety of tocilizumab, an interleukin-6 receptor antibody, in patients with adult-onset Still's disease. Methods: In this double-blind, randomised, placebo-controlled phase III trial, 27 patients with adult-onset Still's disease refractory to glucocorticoids were randomised to tocilizumab at a dose of 8 mg/kg or placebo given intravenously every 2 weeks during the 12-week, double-blind phase. Patients received open-label tocilizumab for 40 weeks subsequently. The primary outcome was American College of Rheumatology (ACR) 50 response at week 4. The secondary outcomes included ACR 20/50/70, systemic feature score, glucocorticoid dose and adverse events at each point. Results: In the full analysis set, ACR50 response at week 4 was achieved in 61.5% (95% CI 31.6 to 86.1) in the tocilizumab group and 30.8% (95% CI 9.1 to 61.4) in the placebo group (p=0.24). The least squares means for change in systemic feature score at week 12 were -4.1 in the tocilizumab group and -2.3 in the placebo group (p=0.003). The dose of glucocorticoids at week 12 decreased by 46.2% in the tocilizumab group and 21.0% in the placebo group (p=0.017). At week 52, the rates of ACR20, ACR50 and ACR70 were 84.6%, 84.6% and 61.5%, respectively, in both groups. Serious adverse events in all participants who received one dose of tocilizumab were infections, aseptic necrosis in the hips, exacerbation of adult-onset Still's disease, drug eruption and anaphylactic shock. Conclusion: The study suggests that tocilizumab is effective in adult-onset Still's disease, although the primary endpoint was not met and solid conclusion was not drawn.

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Multi-omics monitoring of drug response in rheumatoid arthritis in pursuit of molecular remission

Tasaki S., Suzuki K., Kassai Y., Takeshita M., Murota A., Kondo Y., Ando T., Nakayama Y., Okuzono Y., Takiguchi M., Kurisu R., Miyazaki T., Yoshimoto K., Yasuoka H., Yamaoka K., Morita R., Yoshimura A., Toyoshiba H., Takeuchi T.

Nature Communications （Nature Communications） 9 （ 1 ） 2755 2018年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2041-1723

© 2018 The Author(s). Sustained clinical remission (CR) without drug treatment has not been achieved in patients with rheumatoid arthritis (RA). This implies a substantial difference between CR and the healthy state, but it has yet to be quantified. We report a longitudinal monitoring of the drug response at multi-omics levels in the peripheral blood of patients with RA. Our data reveal that drug treatments alter the molecular profile closer to that of HCs at the transcriptome, serum proteome, and immunophenotype level. Patient follow-up suggests that the molecular profile after drug treatments is associated with long-term stable CR. In addition, we identify molecular signatures that are resistant to drug treatments. These signatures are associated with RA independently of known disease severity indexes and are largely explained by the imbalance of neutrophils, monocytes, and lymphocytes. This high-dimensional phenotyping provides a quantitative measure of molecular remission and illustrates a multi-omics approach to understanding drug response.

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IL-6, IL-17 and Stat3 are required for auto-inflammatory syndrome development in mouse

Oike T., Kanagawa H., Sato Y., Kobayashi T., Nakatsukasa H., Miyamoto K., Nakamura S., Kaneko Y., Kobayashi S., Harato K., Yoshimura A., Iwakura Y., Takeuchi T., Matsumoto M., Nakamura M., Niki Y., Miyamoto T.

Scientific Reports （Scientific Reports） 8 （ 1 ） 15783 2018年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2045-2322

© 2018, The Author(s). Auto-inflammatory syndrome, a condition clinically distinct from rheumatoid arthritis, is characterized by systemic inflammation in tissues such as major joints, skin, and internal organs. Autonomous innate-immune activation is thought to promote this inflammation, but underlying pathological mechanisms have not been clarified nor are treatment strategies established. Here, we newly established a mouse model in which IL-1 signaling is conditionally activated in adult mice (hIL-1 cTg) and observed phenotypes similar to those seen in auto-inflammatory syndrome patients. In serum of hIL-1 cTg mice, IL-6 and IL-17 levels significantly increased, and signal transducer and activator of transcription 3 (Stat3) was activated in joints. When we crossed hIL-1 cTg with either IL-6- or IL-17-deficient mice or with Stat3 conditional knockout mice, phenotypes seen in hIL-1 cTg mice were significantly ameliorated. Thus, IL-6, IL-17 and Stat3 all represent potential therapeutic targets for this syndrome.

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Tocilizumab in patients with adult-onset still's disease refractory to glucocorticoid treatment: A randomised, double-blind, placebo-controlled phase III trial

Kaneko Y., Kameda H., Ikeda K., Ishii T., Murakami K., Takamatsu H., Tanaka Y., Abe T., Takeuchi T.

Annals of the Rheumatic Diseases （Annals of the Rheumatic Diseases） 77 （ 12 ） 1720 - 1729 2018年12月

研究論文（学術雑誌）, 査読有り, ISSN 00034967

© © Author(s) (or their employer(s)) 2018. Objective To evaluate the efficacy and safety of tocilizumab, an interleukin-6 receptor antibody, in patients with adult-onset Still's disease. Methods In this double-blind, randomised, placebo-controlled phase III trial, 27 patients with adult-onset Still's disease refractory to glucocorticoids were randomised to tocilizumab at a dose of 8 mg/kg or placebo given intravenously every 2 weeks during the 12-week, double-blind phase. Patients received open-label tocilizumab for 40 weeks subsequently. The primary outcome was American College of Rheumatology (ACR) 50 response at week 4. The secondary outcomes included ACR 20/50/70, systemic feature score, glucocorticoid dose and adverse events at each point. Results In the full analysis set, ACR50 response at week 4 was achieved in 61.5% (95% CI 31.6 to 86.1) in the tocilizumab group and 30.8% (95% CI 9.1 to 61.4) in the placebo group (p=0.24). The least squares means for change in systemic feature score at week 12 were -4.1 in the tocilizumab group and -2.3 in the placebo group (p=0.003). The dose of glucocorticoids at week 12 decreased by 46.2% in the tocilizumab group and 21.0% in the placebo group (p=0.017). At week 52, the rates of ACR20, ACR50 and ACR70 were 84.6%, 84.6% and 61.5%, respectively, in both groups. Serious adverse events in all participants who received one dose of tocilizumab were infections, aseptic necrosis in the hips, exacerbation of adult-onset Still's disease, drug eruption and anaphylactic shock. Conclusion The study suggests that tocilizumab is effective in adult-onset Still's disease, although the primary endpoint was not met and solid conclusion was not drawn.

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Abatacept in combination with methotrexate in Japanese biologic-naive patients with active rheumatoid arthritis: A randomised placebocontrolled phase IV study

Matsubara T., Inoue H., Nakajima T., Tanimura K., Sagawa A., Sato Y., Osano K., Nagano S., Ueki Y., Hanyu T., Hashizume K., Amano N., Tanaka Y., Takeuchi T.

RMD Open （RMD Open） 4 （ 2 ） e000813 2018年12月

研究論文（学術雑誌）, 査読有り, ISSN 2056-5933

© Author(s) (or their employer(s)) 2018. Objectives: To evaluate efficacy and safety of abatacept+methotrexate (MTX) in biologic-naive, anticitrullinated protein antibody (ACPA)-positive Japanese patients with active rheumatoid arthritis (RA) and early erosion versus placebo+MTX. Methods: In this phase IV, multicentre, double-blind study (NCT01758198), patients were randomised (1:1) to receive intravenous abatacept (~10 mg/kg) or placebo, plus MTX (≥6 mg/week). Primary efficacy objectives were to compare American College of Rheumatology 20 (ACR20) response rates at week 16 and mean change from baseline in van der Heijde-modified total Sharp score (vdH-mTSS) at week 24 between abatacept+MTX and placebo+MTX groups. Results: Overall, 203 and 202 patients received abatacept+MTX and placebo+MTX, respectively. At week 16, ACR20 response rates were higher in the abatacept (75.4%) versus placebo group (27.7%; p<0.001). Mean change from baseline in vdH-mTSS at week 24 was 0.84 in the abatacept and 1.26 in the placebo group (p=0.017). Radiographic nonprogression rates (change in vdH-mTSS≤smallest detectable change (2.4)) were 88.1% and 75.4% in abatacept and placebo groups, respectively. Adjusted mean change from baseline in Disease Activity Score 28 (C-reactive protein) (DAS28 (CRP)) at week 16 demonstrated a numerically greater reduction in the abatacept versus placebo group. Proportions of patients with DAS28 (CRP), Simplified Disease Activity Index and Clinical Disease Activity Index remission up to week 52 were higher in the abatacept versus placebo group. The abatacept safety profile was consistent with previous observations. Conclusions: C ompared with MTX alone, abatacept+MTX improved clinical symptoms and inhibited structural damage progression in ACPA-positive, Japanese patients with RA, early erosion and inadequate response to MTX.

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Clinical and Immunological Features of Anti-centromere Antibody-Positive Primary Sjogren's Syndrome

Tsukamoto Masako, Suzuki Katsuya, Takeuchi Tsutomu

RHEUMATOLOGY AND THERAPY 5 （ 2 ） 499 - 505 2018年12月

研究論文（学術雑誌）, 査読有り, ISSN 2198-6576

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Clinical and Immunological Features of Anti-centromere Antibody-Positive Primary Sjögren's Syndrome.

Tsukamoto M, Suzuki K, Takeuchi T

Rheumatology and therapy 5 （ 2 ） 499 - 505 2018年12月

研究論文（学術雑誌）, 査読有り, ISSN 2198-6576

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Phenotype of Platelets Are Altered and Activated in Circulation of Patients with Systemic Sclerosis

Yasuoka Hidekata, Sakata Komei, Yoshimoto Keiko, Takeuchi Tsutomu

BLOOD 132 2018年11月

研究論文（学術雑誌）, 査読有り, ISSN 0006-4971

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Successful rituximab treatment of granulomatosis with polyangiitis with cranial neuropathies

Nakazawa Maho, Suzuki Katsuya, Yasuoka Hidekata, Yamaoka Kunihiro, Takeuchi Tsutomu

INFLAMMATION AND REGENERATION 38 20 2018年11月

研究論文（学術雑誌）, 査読有り, ISSN 1880-8190

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Response to e-letter: 'Tocilizumab in patients with adult-onset Still's disease refractory to glucocorticoid treatment' by Lee.

Kaneko Y, Kameda H, Ikeda K, Ishii T, Murakami K, Takamatsu H, Tanaka Y, Abe T, Takeuchi T

Annals of the rheumatic diseases 2018年11月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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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: A post hoc analysis of overall and Japanese results from phase 3 clinical trials

Kaneko Y., Takeuchi T., Cai Z., Sato M., Awakura K., Gaich C., Zhu B., Guo J., Tanaka Y.

Modern Rheumatology （Modern Rheumatology） 28 （ 6 ） 960 - 967 2018年11月

研究論文（学術雑誌）, 査読有り, ISSN 14397595

© 2018, © 2018 Japan College of Rheumatology. Published by Informa UK Limited, trading as Taylor & Francis Group. 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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Efficacy and safety of sirukumab in Japanese patients with moderate to severe rheumatoid arthritis inadequately controlled by disease modifying anti-rheumatic drugs: Subgroup analysis of a phase 3 study

Takeuchi T., Tanaka Y., Yamanaka H., Harigai M., Nakano T., Akagi K., Ukyo Y., Hsu B.

Modern Rheumatology （Modern Rheumatology） 28 （ 6 ） 941 - 949 2018年11月

研究論文（学術雑誌）, 査読有り, ISSN 14397595

© 2018, © 2018 Japan College of Rheumatology. Published by Informa UK Limited, trading as Taylor & Francis Group. Objective: To evaluate the efficacy and safety of sirukumab in Japanese patients with active rheumatoid arthritis (RA) uncontrolled by disease-modifying antirheumatic drugs. Methods: This subgroup analysis based on a double-blind, placebo-controlled, 52-week phase 3 study (SIRROUND-D) assessed American College of Rheumatology (ACR) 20 response at week 16 and van der Heijde-modified Sharp score (vdH-S) at week 52 (coprimary endpoints). Results: A total of 168 (Japanese)/1670 patients received sirukumab 50 mg/4 weeks (q4w, n = 58), 100 mg/every 2 weeks (q2w, n = 54), or placebo (n = 56) subcutaneously. Significantly more patients achieved ACR20 response at week 16 with sirukumab (50 mg q4w: 69.0%; 100mg q2w: 66.7%) vs. placebo (21.4%; p <.001). Median change from baseline in total vdH-S score at week 52 was significantly lower with sirukumab (50 mg q4w: 0.3, p =.024; 100 mg q2w: 0.0, p =.002) vs. placebo (1.3). Sirukumab consistently showed greater improvements in secondary endpoints at weeks 24 and 52. Nasopharyngitis, elevated liver enzymes, injection site erythema and upper respiratory tract infections were the common treatment-emergent adverse events (TEAEs). Incidences of TEAEs and serious AEs were consistent between sirukumab groups through week 52. Conclusion: Sirukumab showed clinically meaningful improvements consistent with significant improvements in the global study. No new safety signals were observed.

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Investigating sirukumab for rheumatoid arthritis: 2-year results from the phase III SIRROUND-D study

Thorne C., Takeuchi T., Karpouzas G., Sheng S., Kurrasch R., Fei K., Hsu B.

RMD Open （RMD Open） 4 （ 2 ） e000731 2018年11月

研究論文（学術雑誌）, 査読有り, ISSN 2056-5933

© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. Objectives The phase III, multicentre, randomised, double-blind, placebo-controlled, parallel-group SIRROUND-D study evaluated long-term efficacy and safety of the interleukin (IL)-6 inhibitor, sirukumab, in patients with active rheumatoid arthritis (RA) refractory to disease-modifying antirheumatic drugs (DMARDs). Methods Patients were randomised 1:1:1 to sirukumab 100mg every 2 weeks (q2w), 50mg every 4 weeks or placebo q2w subcutaneously. Patients initially randomised to placebo were rerandomised at Weeks 18, 40 or 52 to one of the sirukumab groups until Week 104. Results Of 1670 randomised patients, 1402 were included in the full analysis set and 1269 in the radiographic analysis set at Week 104. American College of Rheumatology scores, Disease Activity Score based on C-reactive protein, Clinical Disease Activity Index and clinically meaningful improvements in patient-reported outcomes were sustained at Week 104 among patients initially randomised to sirukumab. Placebo patients subsequently rerandomised to sirukumab showed clinical improvements at Week 104 that were comparable to results among patients initially randomised to sirukumab. Radiographic progression from Week 52 to Week 104 was comparable between all groups whether initially randomised to sirukumab or subsequently rerandomised to sirukumab from placebo. No new safety signals were identified in the extended exposure period compared with the initial 52 weeks of treatment. Conclusions Sirukumab treatment resulted in sustained reductions in clinical signs and symptoms and minimal progression in radiographic damage over 2 years among patients with RA refractory to DMARDs. The safety profile of sirukumab was as expected for an anti-IL-6 agent, with no new signals reported.

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Beneficial effects of Denosumab on bone loss and bone erosion from results of long-term treatment in the phase 3, DESIRABLE study in patients with rheumatoid arthritis (RA) on background csDMARDs

Tanaka Yoshiya, Soen Satoshi, Yamanaka Hisashi, Yoneda Toshiyuki, Tanaka Sakae, Nitta Takaya, Okubo Naoki, Genant Harry, Van der Heijde Desiree, Takeuchi Tsutomu

JOURNAL OF BONE AND MINERAL RESEARCH 33 90 - 90 2018年11月

研究論文（学術雑誌）, 査読有り, ISSN 0884-0431

Safety and effectiveness of abatacept in Japanese non-elderly and elderly patients with rheumatoid arthritis in an all-cases post-marketing surveillance.

Harigai M, Ishiguro N, Inokuma S, Mimori T, Ryu J, Takei S, Takeuchi T, Tanaka Y, Takasaki Y, Yamanaka H, Yoshizawa Y, Chinen I, Nakao T, Koike T

Modern rheumatology 1 - 9 2018年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objectives: To investigate the safety, effectiveness, and risk-benefit balance of intravenous abatacept (ABA) in non-elderly (<65 years: NEG) and elderly (≥65 years: EG) rheumatoid arthritis patients. Methods: This sub-analysis of an all-cases postmarketing surveillance in Japan assessed safety in all enrolled patients and effectiveness in those with Disease Activity Score 28 based on C-reactive protein (DAS28-CRP) measurements at ≥2 time points including baseline. Risk-benefit was evaluated based on infections and DAS28-CRP improvement >1.2. Results: The NEG and EG of the safety analysis set comprised 2,170 and 1,712 patients, respectively; corresponding 6-month ABA retention rates were 80.2% and 77.1%. The NEG had fewer adverse drug reactions (14.5% vs. 17.2%, p =.021) and infections (4.8% vs. 7.2%, p =.002) than the EG. DAS28-CRP changed similarly between groups. The proportion of patients with low-risk/high-benefit and high-risk/low-benefit were 33.1% and 6.9% (NEG) and 29.7% and 9.0% (EG). Low-risk/high-benefit patients were younger, had shorter disease duration and fewer comorbidities, and were with less use of oral glucocorticoid and prior biologics, more use of methotrexate and higher DAS28-CRP than high-risk/low-benefit patients at baseline. Conclusion: ABA was well tolerated and similarly efficacious in the EG and NEG. Identification of factors related to low-risk/high-benefit may aid appropriate patient selection.

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Effectiveness of tacrolimus on IgG4-related disease.

Takanashi S, Kaneko Y, Takeuchi T

Modern rheumatology 1 - 10 2018年10月

研究論文（学術雑誌）, 査読有り, ISSN 1439-7595

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Association Between Reappearance of Myeloperoxidase–Antineutrophil Cytoplasmic Antibody and Relapse in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis: Subgroup Analysis of Nationwide Prospective Cohort Studies

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

Arthritis and Rheumatology （Arthritis and Rheumatology） 70 （ 10 ） 1626 - 1633 2018年10月

研究論文（学術雑誌）, 査読有り, ISSN 23265191

© 2018, American College of Rheumatology 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: HAWK study postmarketing surveillance in Japan.

Tanaka Y, Mimori T, Yamanaka H, Nakajima R, Morita K, Kimura J, Takeuchi T

Modern rheumatology 1 - 9 2018年09月

研究論文（学術雑誌）, 査読有り, ISSN 1439-7595

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Dose reduction of baricitinib in patients with rheumatoid arthritis achieving sustained disease control

Takeuchi Tsutomu, Genovese Mark C., Haraoui Boulos, Li Zhanguo, Xie Li, Klar Rena, Pinto-Correia Ana, Otawa Susan, Lopez-Romero Pedro, De La Torre Inmaculada, Macias William, Rooney Terence P., Smolen Josef S.

Annals of the rheumatic diseases 2018年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

Objectives: This study investigated the effects of dose step-down in patients with rheumatoid arthritis (RA) who achieved sustained disease control with baricitinib 4 mg once a day. Methods: Patients who completed a baricitinib phase 3 study could enter a long-term extension (LTE). In the LTE, patients who received baricitinib 4 mg for ≥15 months and maintained CDAI low disease activity (LDA) or remission (REM) were blindly randomised to continue 4 mg or taper to 2 mg. Patients could rescue (to 4 mg) if needed. Efficacy and safety were assessed through 48 weeks. Results: Patients in both groups maintained LDA (80% 4 mg; 67% 2 mg) or REM (40% 4 mg; 33% 2 mg) over 48 weeks. However, dose reduction resulted in small, statistically significant increases in disease activity at 12, 24 and 48 weeks. Dose reduction also produced earlier and more frequent relapse (loss of step-down criteria) over 48 weeks compared with 4 mg maintenance (23% 4 mg vs 37% 2 mg, p=0.001). Rescue rates were 10% for baricitinib 4 mg and 18% for baricitinib 2 mg. Dose reduction was associated with a numerically lower rate of non-serious infections (30.6 for baricitinib 4 mg vs 24.9 for 2 mg). Rates of serious adverse events and adverse events leading to discontinuation were similar across groups. Conclusions: In a large randomised, blinded phase 3 study, maintenance of RA control following induction of sustained LDA/REM with baricitinib 4 mg was greater with continued 4 mg than after taper to 2 mg. Nonetheless, most patients tapered to 2 mg could maintain LDA/REM or recapture with return to 4 mg if needed.

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Clinical efficacy, radiographic, and safety results of golimumab monotherapy in Japanese patients with active rheumatoid arthritis despite prior therapy with disease-modifying antirheumatic drugs

Takeuchi Tsutomu, Harigai Masayoshi, Tanaka Yoshiya, Yamanaka Hisashi, Ishiguro Naoki, Yamamoto Kazuhiko, Miyasaka Nobuyuki, Koike Takao, Ukyo Yoshifumi, Ishii Yutaka, Yoshinari Toru, Baker Daniel

Modern Rheumatology 28 （ 5 ） 770 - 779 2018年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objective: Evaluate the safety and efficacy of golimumab through week 120 in Japanese patients with active rheumatoid arthritis (RA) previously treated with DMARDs. Methods: Japanese patients with active RA despite prior DMARDs were randomized to placebo (Group 1, n = 105), golimumab 50 mg (Group 2, n = 101), or golimumab 100 mg (Group 3, n = 102). At week 16, Group 1 patients crossed over to golimumab 50mg; after week 52, a one-time golimumab dose reduction from 100 to 50 mg was permitted. Assessments included ACR20/50/70 responses and good/moderate DAS28-ESR responses. Radiographic progression was assessed with the van der Heijde-modified Sharp (vdH-S) score. Safety and efficacy were assessed through week 120. Results: ACR20 response rates at week 52 in Group 1, Group 2, and Group 3 were 70.6%, 71.4%, and 81.9%, respectively, and maintained through week 104 (87.2%, 85.1%, 88.9%, respectively) and week 120 (86.1%, 87.0%, 89.5%, respectively). Similar trends were observed for ACR50, ACR 70, and DAS28-ESR. Median change in total vdH-S at weeks 52, 104, and 120 ranged from 0.0 to 1.5 across treatment groups. Through week 120, 93.8%/97.1% had an AE with golimumab 50 mg/100 mg, respectively, and 19.7%/11.8% had an SAE. Infections were the most common AE. Conclusion: Clinical response to golimumab 50 mg and 100 mg was maintained over 2 years in Japanese patients with active RA despite prior DMARDs.

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Tocilizumab discontinuation after attaining remission in patients with rheumatoid arthritis who were treated with tocilizumab alone or in combination with methotrexate: Results from a prospective randomised controlled study (the second year of the SURPRISE study)

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

Annals of the Rheumatic Diseases （Annals of the Rheumatic Diseases） 77 （ 9 ） 1268 - 1275 2018年09月

研究論文（学術雑誌）, 査読有り, ISSN 00034967

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. Objective To evaluate the sustained remission and low disease activity after discontinuation of tocilizumab in patients with rheumatoid arthritis who were treated with tocilizumab alone or in combination with methotrexate. Methods The SURPRISE study was a 2-year, open-label randomised controlled study. Among patients who had been randomised to additional tocilizumab (ADD-ON) or switch to tocilizumab (SWITCH) in the first year, those who achieved remission based on the disease activity score for 28 joints (DAS28-ESR<2.6) discontinued tocilizumab at week 52 and were observed for the following 52 weeks. The endpoint of the second year included tocilizumab-free remission and low disease-activity rates, functional outcome, radiological outcomes assessed with the modified total Sharp score (mTSS) and safety. The efficacy of reinstituted tocilizumab/methotrexate was also evaluated. Results A total of 105 patients who achieved remission at week 52 discontinued tocilizumab; 51 in ADD-ON continued methotrexate and 54 in SWITCH received no disease-modifying antirheumatic drugs. Sustained DAS28 low disease-activity rates were significantly higher in ADD-ON than in SWITCH (55%vs27%, p=0.005). Sustained remission rates at week 104 were 24% for ADD-ON and 14% for SWITCH (p=0.29). Radiological progression was comparable between both groups (mTSS; 0.37vs0.64, p=0.36). The restart of tocilizumab induced remission in all except two patients after 36 weeks, irrespective of concomitant methotrexate. Conclusion Sustained low disease activity after tocilizumab discontinuation could be maintained with continued methotrexate in more than half of the patients. Retreatment with tocilizumab led to remission in more than 90% of patients. Trial registration number NCT01120366; Results.

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Reduced Expression of CX3CR1 in Peripheral CD14++CD16+monocytes Is a Novel Feature of Patients with Systemic Lupus Erythematosus

Yoshimoto Keiko, Suzuki Katsuya, Saito Shuntaro, Kikuchi Jun, Takeuchi Tsutomu

ARTHRITIS & RHEUMATOLOGY 70 2018年09月

研究論文（学術雑誌）, 査読有り, ISSN 2326-5191

Sustained Clinical Remission after Discontinuation of Infliximab with a Raising Dose Strategy in Patients with Rheumatoid Arthritis (RRRR study): A Randomized Controlled Trial

Tanaka Yoshiya, Oba Koji, Koike Takao, Miyasaka Nobuyuki, Mimori Tsuneyo, Takeuchi Tsutomu, Hirata Shintaro, Tanaka Eiichi, Yasuoka Hidekata, Kaneko Yuko, Murakami Kosaku, Koga Tomohiro, Nakano Kazuhisa, Amano Koichi, Ushio Kazuyasu, Atsumi Tatsuya, Inoo Masayuki, Hatta Kazuhiro, Mizuki Shinichi, Nagaoka Shohei, Tsunoda Shinichiro, Dobashi Hiroaki, Horie Nao, Sato Norihiro

ARTHRITIS & RHEUMATOLOGY 70 2018年09月

研究論文（学術雑誌）, 査読有り, ISSN 2326-5191

Serum Krebs Von Den Lungen-6 Is a Useful Biomarker for Assessing Activity of Myositis-Associated Interstitial Lung Disease

Takanashi Satoshi, Nishina Naoshi, Nakazawa Maho, Kaneko Yuko, Takeuchi Tsutomu

ARTHRITIS & RHEUMATOLOGY 70 2018年09月

研究論文（学術雑誌）, 査読有り, ISSN 2326-5191

Safety Profile of Baricitinib for the Treatment of Rheumatoid Arthritis up to 6 Years: An Updated Integrated Safety Analysis

Genovese Mark C., Smolen Josef S., Takeuchi Tsutomu, Rooney Terence P., Dickson Christina L., Yang Xiao-Yan, Saifan Chadi, Cardoso Anabela, Issa Maher, Ishii Taeko, Winthrop Kevin

ARTHRITIS & RHEUMATOLOGY 70 2018年09月

研究論文（学術雑誌）, 査読有り, ISSN 2326-5191

Rheumatoid Factor Titer Is Inversely Correlated with ANCA Titer and Relates to Characteristic Manifestations in Patients with Eosinophilic Granulomatosis with Polyangiitis

Inamo Jun, Kaneko Yuko, Ota Yuichiro, Takeuchi Tsutomu

ARTHRITIS & RHEUMATOLOGY 70 2018年09月

研究論文（学術雑誌）, 査読有り, ISSN 2326-5191

A Phase 3, Randomized, Controlled Trial Comparing Upadacitinib Monotherapy to MTX Monotherapy in MTX-Naive Patients with Active Rheumatoid Arthritis

van Vollenhoven Ronald, Takeuchi Tsutomu, Pangan Aileen L., Friedman Alan, Mohamed Mohamed-Eslam, Chen Su, Rischmueller Maureen, Blanco Ricardo, Xavier Ricardo M., Strand Vibeke

ARTHRITIS & RHEUMATOLOGY 70 2018年09月

研究論文（学術雑誌）, 査読有り, ISSN 2326-5191

Longitudinal Efficacy Analysis of Patients with Active Rheumatoid Arthritis and Inadequate Response to Conventional Synthetic Dmards: Response Following Rescue from Baricitinib 2mg to 4mg Once-Daily

Fleischmann Roy, Genovese Mark C., Cardoso Anabela, Sun Luna, Chen Yun-Fei, Walls Chad D., Schlichting Douglas E., Takeuchi Tsutomu, Dougados Maxime, Smolen Josef S., Curtis Jeffrey R.

ARTHRITIS & RHEUMATOLOGY 70 2018年09月

研究論文（学術雑誌）, 査読有り, ISSN 2326-5191

Localization of the Voltage-Gated Sodium Channel 1.7 in Peripheral Monocytes Contributes to Activation of BAFF Signaling in Monocytes of Patients with Primary Sjogren's Syndrome

Yoshimoto Keiko, Ikeda Yumi, Suzuki Katsuya, Takeuchi Tsutomu

ARTHRITIS & RHEUMATOLOGY 70 2018年09月

研究論文（学術雑誌）, 査読有り, ISSN 2326-5191

Efficacy and Safety of the Novel Oral Janus Kinase (JAK) Inhibitor, Peficitinib (ASP015K), in a Phase 3, Double-Blind, Placebo-Controlled, Randomized Study of Patients with RA Who Had an Inadequate Response to Methotrexate

Takeuchi Tsutomu, Tanaka Yoshiya, Tanaka Sakae, Kawakami Atsushi, Iwasaki Manabu, Rokuda Mitsuhiro, Izutsu Hiroyuki, Ushijima Satoshi, Kaneko Yuichiro, Shiomi Teruaki, Yamada Emi

ARTHRITIS & RHEUMATOLOGY 70 2018年09月

研究論文（学術雑誌）, 査読有り, ISSN 2326-5191

Tanaka Yoshiya, Takeuchi Tsutomu, Tanaka Sakae, Kawakami Atsushi, Iwasaki Manabu, Song Yeong Wook, Chen Yi-Hsing, Rokuda Mitsuhiro, Izutsu Hiroyuki, Ushijima Satoshi, Kaneko Yuichiro, Shiomi Teruaki, Yamada Emi

ARTHRITIS & RHEUMATOLOGY 70 2018年09月

研究論文（学術雑誌）, 査読有り, ISSN 2326-5191

Detecting Hand Joint Ankylosis in Radiographic Images Using Deep Learning: A Step in Development of Automatic Radiographic Scoring System for Bone Destruction

Izumi Keisuke, Hashimoto Masahiro, Suzuki Kanata, Endoh Thshio, Doi Kentaro, Iwai Yuki, Jinzaki Masahiro, Ko Shigeru, Takeuchi Tsutomu

ARTHRITIS & RHEUMATOLOGY 70 2018年09月

研究論文（学術雑誌）, 査読有り, ISSN 2326-5191

Clinical and Functional Response to Tofacitinib and Adalimumab in Patients with Rheumatoid Arthritis: Probability Plot Analysis of Results from the ORAL Strategy Trial

Takeuchi Tsutomu, Smolen Josef S., Fleischmann Roy, Iikuni Noriko, Fan Haiyun, Soma Koshika, Akylbekova Ermeg, Hirose Tomohiro

ARTHRITIS & RHEUMATOLOGY 70 2018年09月

研究論文（学術雑誌）, 査読有り, ISSN 2326-5191

Cardiovascular Safety - Update from up to 6 Years of Treatment with Baricitinib in Rheumatoid Arthritis Clinical Trials

Weinblatt Michael, Taylor Peter C., Burmester Gerd R., Saifan Chadi, Walls Chad D., Issa Maher, Rooney Terence P., Takeuchi Tsutomu

ARTHRITIS & RHEUMATOLOGY 70 2018年09月

研究論文（学術雑誌）, 査読有り, ISSN 2326-5191

A Phase III Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Abatacept or Placebo on Standard of Care in Patients with Active Class III or IV Lupus Nephritis

Dooley Mary A., Appel Gerald B., Furie Richard, Wofsy David, Takeuchi Tsutomu, Malvar Ana, Doria Andrea, Romero-Diaz Juanita, Chan Tak Mao, Elegbe Ayanbola, Jayne David, Maldonado Michael A.

ARTHRITIS & RHEUMATOLOGY 70 2018年09月

研究論文（学術雑誌）, 査読有り, ISSN 2326-5191

Risk factors for abnormal hepatic enzyme elevation by methotrexate treatment in patients with rheumatoid arthritis: A hospital based-cohort study

Hakamata J., Hashiguchi M., Kaneko Y., Yamaoka K., Shimizu M., Maruyama J., Takeuchi T., Mochizuki M.

Modern Rheumatology （Modern Rheumatology） 28 （ 4 ） 611 - 620 2018年07月

研究論文（学術雑誌）, 査読有り, ISSN 14397595

© 2017, © 2017 Japan College of Rheumatology. Objectives: Methotrexate (MTX) is used as first-line treatment of rheumatoid arthritis (RA) worldwide. Large interindividual differences in MTX effectiveness and safety occur, and the most frequent adverse reaction is hepatotoxicity, although the main cause remains unknown. We investigated factors associated with MTX-induced hepatic enzyme elevation in a hospital-based cohort study. Methods: Study participants were 114 Japanese adult RA outpatients prescribed MTX. Sixteen types of single-nucleotide polymorphisms were investigated using real-time PCR. Patient characteristics were collected from the electronic medical records. The onset of MTX-induced abnormal hepatic enzyme elevation was defined according to deviation from normal liver enzyme reference values during treatment. The observation period was 1 year after beginning MTX. Associations between MTX-induced hepatic enzyme elevation and patient characteristics were evaluated using the multivariate logistic regression model. Results: Thirty-two patients experienced MTX-induced abnormal hepatic enzyme elevation. In multivariate analysis, MTX dosage, estimated glomerular filtration rate (eGFR), and genetic polymorphisms of ABCB1 3435C>T and ATIC 347C>G were associated with abnormal hepatic enzyme elevation. Conclusions: MTX-induced abnormal hepatic enzyme elevation in Japanese RA patients was associated with dosage and eGFR as nongenetic factors, and with ABCB1 3435C>T and ATIC 347C>G as genetic factors in this hospital-based cohort study.

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Secukinumab after anti-tumour necrosis factor-α therapy: a phase III study in active rheumatoid arthritis

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

Scandinavian Journal of Rheumatology （Scandinavian Journal of Rheumatology） 47 （ 4 ） 276 - 281 2018年07月

研究論文（学術雑誌）, 査読有り, ISSN 03009742

© 2018, © 2018 Informa Healthcare on license from Scandinavian Rheumatology Research Foundation. 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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Efficacy and safety of baricitinib in Japanese patients with rheumatoid arthritis: Subgroup analyses of four multinational phase 3 randomized trials

Tanaka Y., Atsumi T., Amano K., Harigai M., Ishii T., Kawaguchi O., Rooney T., Akashi N., Takeuchi T.

Modern Rheumatology （Modern Rheumatology） 28 （ 4 ） 583 - 591 2018年07月

研究論文（学術雑誌）, 査読有り, ISSN 14397595

© 2017, © 2017 Japan College of Rheumatology. Published by Informa UK Limited, trading as Taylor & Francis Group. Objectives: To evaluate efficacy/safety of baricitinib for rheumatoid arthritis (RA) in Japanese subpopulations from four phase 3 studies, and assess whether results in these subpopulations are consistent with the overall study populations. Methods: Subgroup analyses (394 patients) of four phase 3 randomized controlled trials: RA-BEGIN [no or limited treatment with disease-modifying antirheumatic drugs (DMARDs)], RA-BEAM [inadequate response (IR) to methotrexate], RA-BUILD [IR to conventional synthetic DMARDs (csDMARDs)], and RA-BEACON (IR to tumor necrosis factor inhibitors receiving csDMARDs). Results: For American College of Rheumatology 20% improvement (ACR20) response rate, Japanese patients receiving baricitinib 4-mg showed similar improvement compared to methotrexate at Week 24 (72 versus 69%; RA-BEGIN), and greater improvement compared with placebo at Week 12 (67 versus 34%; RA-BEAM). Japanese patients receiving baricitinib 4-mg also showed greater improvement compared with placebo at Week 12 in RA-BUILD and RA-BEACON. Across all studies, baricitinib was well-tolerated, with no deaths and one malignancy. In RA-BEGIN and RA-BEAM, herpes zoster rates were higher for Japanese patients than for overall populations; all events were mild/moderate. Conclusion: Data for baricitinib, with/without methotrexate, in Japanese subpopulations across all stages of the RA treatment continuum accord with the efficacy/safety profile in overall study populations. Baricitinib appears to be similarly effective in Japanese patients.

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Safety Profile of Baricitinib for the Treatment of Rheumatoid Arthritis up to 5.5 Years: An Updated Integrated Safety Analysis

Keystone Edward, Genovese Mark, Smolen Josef, Takeuchi Tsutomu, Hyslop David, Macias William, Rooney Terence, Chen Lei, Dickson Christina, Camp Jennifer, Cardillo Tracy, Ishii Taeko, Winthrop Kevin, Otawa Susan

JOURNAL OF RHEUMATOLOGY 45 （ 7 ） 1003 - 1003 2018年07月

研究論文（学術雑誌）, 査読有り, ISSN 0315-162X

Dose Reduction of Baricitinib in Patients with Rheumatoid Arthritis Achieving Sustained Disease Control: Results of a Prospective Study

Takeuchi Tsutomu, Genovese Mark, Haraoui Boulos, Li Zhanguo, Xie Li, Klar Rena, Correia Ana Pinto, Otawa Susan, Lopez-Romero Pedro, de la Torre Inmaculada, Rooney Terence, Smolen Josef

JOURNAL OF RHEUMATOLOGY 45 （ 7 ） 1054 - 1054 2018年07月

研究論文（学術雑誌）, 査読有り, ISSN 0315-162X

Takanashi S., Akiyama M., Suzuki K., Otomo K., Takeuchi T.

Medicine (United States) （Medicine (United States)） 97 （ 22 ） e10935 2018年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0025-7974

© 2018 the Author(s). Published by Wolters Kluwer Health, Inc. Rationale: Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory disease characterized by elevated serum IgG4 levels with infiltration of IgG4+ plasma cells and severe fibrosis in affected tissues. Recently, idiopathic fibrosing mediastinitis (FM), an extremely rare fibroinflammatory disorder, has been recognized as a form of IgG4-RD. As IgG4-RD can be treated by glucocorticoids, identification of the etiology of FM by surgical biopsy is essential; however, mediastinal biopsy is often difficult. We report 2 cases of IgG4-related FM successfully diagnosed with computed tomography (CT)-guided percutaneous needle biopsy. Patient concerns: Case 1 was a 66-year-old woman with elevated serum C-reactive protein without any symptoms and case 2 was 78-year-old woman with abnormal mediastinal contour on chest x-ray. By further work-up, both cases were found to have mediastinitis accompanied by elevated serum IgG4. CT-guided percutaneous needle biopsy revealed massive infiltration of IgG4+plasma cells along with storiform fibrosis. Diagnosis: IgG4-related FM. Interventions: Glucocorticoid therapy. Outcome: The treatment resulted in significant improvement of the lesions after 3 months. Lessons: Early recognition and diagnosis of IgG4-related FM is essential because a delay in appropriate treatment initiation leads to progressive fibrosis with irreversible organ damage and poor prognosis. Our cases highlight CT-guided percutaneous needle biopsy as a promising option for histological examination in patients with IgG4-related FM.

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POSSIBLE INVOLVEMENT OF BAFF AND MATRIXMETALLOPROTEINASE-9 IN THE ACTIVATION OF MONOCYTES OF PATIENTS WITH PRIMARY SJOGREN'S SYNDROME

Yoshimoto K., Suzuki K., Takeuchi T.

ANNALS OF THE RHEUMATIC DISEASES 77 882 - 882 2018年06月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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TOCILIZUMAB DISCONTINUATION AFTER ATTAINING REMISSION IN PATIENTS WITH RHEUMATOID ARTHRITIS WHO WERE TREATED WITH TOCILIZUMAB ALONE OR IN COMBINATION WITH METHOTREXATE: RESULTS FROM A PROSPECTIVE, RANDOMISED, CONTROLLED STUDY (THE SECOND YEAR OF THE SURPRISE STUDY)

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

ANNALS OF THE RHEUMATIC DISEASES 77 105 - 106 2018年06月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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THE EFFECTIVENESS OF SHORT TRAINING IN PSYCHOLOGICAL SUPPORT FOR NURSES IN RHEUMATIC CARE

Fusama M., Nakahara H., Higashi K., Mori M., Mabuchi M., Sakai Y., Motonaga T., Takeuchi T.

ANNALS OF THE RHEUMATIC DISEASES 77 1794 - 1795 2018年06月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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SERUM KL-6 IS A STRONG PREDICTOR FOR RELAPSE OF MYOSITIS-ASSOCIATED INTERSTITIAL LUNG DISEASE

Takanashi S., Nishina N., Nakazawa M., Kaneko Y., Takeuchi T.

ANNALS OF THE RHEUMATIC DISEASES 77 760 - 760 2018年06月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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RISK FACTORS FOR CYTOMEGALOVIRUS REACTIVATION IN PATIENTS WITH CONNECTIVE-TISSUE DISEASE; SINGLE-CENTREPROSPECTIVE COHORT STUDY

Ota Y., Kaneko Y., Takeuchi T.

ANNALS OF THE RHEUMATIC DISEASES 77 1766 - 1766 2018年06月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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RHEUMATOID FACTOR POSITIVITY IS RELATED TO CLINICAL AND IMMUNOLOGICAL CHARACTERISTICS IN PATIENTS WITH EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS

Inamo J., Kaneko Y., Ohta Y., Takeuchi T.

ANNALS OF THE RHEUMATIC DISEASES 77 1481 - 1481 2018年06月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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RESIDUAL SYNOVITIS IN ANKLES AND FEET DETECTED BY ULTRASONOGRAPHY IN PATIENTS WITH RHEUMATOID ARTHRITIS

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

ANNALS OF THE RHEUMATIC DISEASES 77 300 - 300 2018年06月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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A LOW MOLECULAR WEIGHT BAFF SIGNALLINGINHIBITOR, BIK-13, AMELIORATES B CELL ACTIVATION IN VITRO AND IN VIVO AUTOIMMUNE MODELS AND CONSEQUENTLY SUPPRESSES PRODUCTION OF IGG AND CYTOKINES

Yoshimoto K., Seki N., Suzuki K., Sugahara K., Chiba K., Takeuchi T.

ANNALS OF THE RHEUMATIC DISEASES 77 134 - 134 2018年06月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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INFLAMMATORY FINDINGS ON ULTRASOUND AND MRI CAN PREDICT FUTURE DEVELOPMENT OF RHEUMATOID ARTHRITIS IN PATIENTS WITH SERONEGATIVE, UNDIFFERENCIATED ARTHRITIS

Kondo Y., Kaneko Y., Inoue Y., Takahashi C., Sakata K., Yamaoka K., Sato S., Takeuchi T.

ANNALS OF THE RHEUMATIC DISEASES 77 1711 - 1711 2018年06月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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IMPAIRED ACTIVATION OF ATAXIA-TELANGIECTASIA MUTATED PROTEIN KINASE IN IMMUNE CELLS IS ASSOCIATED WITH CLINICAL FEATURES IN PATIENTS WITH SYSTEMIC SCLEROSIS

Sakata K., Yasuoka H., Yoshimoto K., Yamaoka K., Takeuchi T.

ANNALS OF THE RHEUMATIC DISEASES 77 1281 - 1282 2018年06月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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HEPATITIS B VIRUS REACTIVATION IN PATIENTS WITH RHEUMATOID ARTHRITIS TREATED WITH BARICITINIB: POST-HOC ANALYSIS FROM CLINICAL TRIALS

Harigai M., Winthrop K., Takeuchi T., Hsieh T. -Y., Chen Y. -M., Smolen J. S., Burmester G. R., Walls C., Wu W. -S., Dickson C., Liao R., Genovese M. C.

ANNALS OF THE RHEUMATIC DISEASES 77 584 - 585 2018年06月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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EFFECTS OF DENOSUMAB, A SUBCUTANEOUS RANKL INHIBITOR, ON THE PROGRESSION OF STRUCTURAL DAMAGE IN JAPANESE PATIENTS WITH RHEUMATOID ARTHRITIS TREATED WITH CSDMARDS: RESULT FROM THE LONG-TERM TREATMENT OF PHASE 3, DESIRABLE STUDY

Takeuchi T., Tanaka Y., Soen S., Yamanaka H., Yoneda T., Tanaka S., Nitta T., Okubo N., Genant H., van der Heijde D.

ANNALS OF THE RHEUMATIC DISEASES 77 947 - 948 2018年06月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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DOSE REDUCTION OF BARICITINIB IN PATIENTS WITH RHEUMATOID ARTHRITIS ACHIEVING SUSTAINED DISEASE CONTROL: RESULTS OF A PROSPECTIVE STUDY

Takeuchi T., Genovese M. C., Haraoui B., Li Z., Xie L., Klar R., Correia A. P., Otawa S., Lopez-Romero P., De la Torre I., Rooney T., Smolen J. S.

ANNALS OF THE RHEUMATIC DISEASES 77 988 - 989 2018年06月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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CLINICAL AND FUNCTIONAL RESPONSE TO TOFACITINIB AND ADALIMUMAB IN PATIENTS WITH RHEUMATOID ARTHRITIS: PROBABILITY PLOT ANALYSIS OF RESULTS FROM THE ORAL STRATEGY TRIAL

Takeuchi T., Smolen J. S., Fleischmann R., Iikuni N., Fan H., Soma K., Akylbekova E., Hirose T.

ANNALS OF THE RHEUMATIC DISEASES 77 987 - 988 2018年06月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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CHARACTERISTICS OF RECENT ELDERLY-ONSET RHEUMATOID ARTHRITIS PATIENTS

Oshige T., Kaneko Y., Takeuchi T.

ANNALS OF THE RHEUMATIC DISEASES 77 566 - 566 2018年06月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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BIOMARKERS FOR RELAPSE IN PATIENTS WITH ADULT ONSET STILL'S DISEASE TREATED WITH IL-6 INHIBITOR

Yamada H., Kaneko Y., Takeuchi T.

ANNALS OF THE RHEUMATIC DISEASES 77 853 - 853 2018年06月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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ARYL HYDROCARBON RECEPTOR EXPRESSION IS ASSOCIATED WITH LUNG INVOLVEMENT IN SYSTEMIC SCLEROSIS

Takei H., Yasuoka H., Yoshimoto K., Yamaoka K., Takeuchi T.

ANNALS OF THE RHEUMATIC DISEASES 77 738 - 738 2018年06月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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ANALYSIS OF SYMPTOMS IN VERY EARLY PHASE IN PATIENTS WITH ADULT-ONSET STILL'S DISEASE

Tamai H., Kaneko Y., Takeuchi T.

ANNALS OF THE RHEUMATIC DISEASES 77 1743 - 1744 2018年06月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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ACTIVATED PLATELETS ARE INCREASED IN CIRCULATION OF PATIENTS WITH SYSTEMIC SCLEROSIS AND ASSOCIATED WITH CLINICAL CHARACTERISTICS

Yasuoka H., Sakata K., Yoshimoto K., Yamaoka K., Kuwana M., Takeuchi T.

ANNALS OF THE RHEUMATIC DISEASES 77 1281 - 1281 2018年06月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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A PHASE 2B/3 RANDOMISED, PLACEBO-CONTROLLED, DOUBLE-BLIND STUDY OF UPADACITINIB, A SELECTIVE JAK1 INHIBITOR, IN JAPANESE PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS AND INADEQUATE RESPONSE TO CONVENTIONAL SYNTHETIC DMARDS

Tanaka Y., Takeuchi T., Yamaoka K., Oribe M., Kawano M., Zhou Y., Othman A. A., Pangan A. L., Kitamura S., Matsuda N., Meerwein S., Kameda H.

ANNALS OF THE RHEUMATIC DISEASES 77 991 - 992 2018年06月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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Interleukin-4 contributes to the shift of balance of IgG subclasses toward IgG4 in IgG4-related disease

竹内勤

Cytokine （Cytokine） 110 416 - 419 2018年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 10434666

© 2018 IgG4-related disease (IgG4-RD) is a systemic disorder characterized by elevated serum IgG4 level, which is mediated by T follicular helper 2 (Tfh2) cell. However, the cytokines responsible for enhancing IgG4 production remain unclear in IgG4-RD. The aim of this study was to identify responsible Tfh2-related cytokines (interleukin (IL)-4 and IL-21) for enhancing IgG4 production in IgG4-RD. Peripheral blood mononuclear cells obtained from consecutive patients with active, untreated IgG4-RD and healthy controls were examined. The production of both IgG and IgG4 were significantly increased by stimulation with IL-4 alone as well as IL-21 alone compared to background stimulation with anti-CD40 antibody in IgG4-RD. On the other hand, the IgG4/IgG ratio was statistically higher by stimulation with IL-4 alone compared to the other Tfh2-related cytokines including IL-21 in IgG4-RD. IgG4 production was not increased by stimulation with IL-4 in healthy controls. These results suggest that IL-4 can contribute to the shift of balance of IgG subclasses toward IgG4 compared to the other Tfh2-related cytokines in IgG4-RD.

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Tocilizumab discontinuation after attaining remission in patients with rheumatoid arthritis who were treated with tocilizumab alone or in combination with methotrexate

Kaneko Yuko, Kato Masaru, Tanaka Yoshiya, Inoo Masayuki, Kobayashi-Haraoka Hitomi, Amano Koichi, Miyata Masayuki, Murakawa Yohko, Yasuoka Hidekara, Hirata Shintaro, Tanaka Eiichi, Miyasaka Nobuyuki, Yamanaka Hisashi, Yamamoto Kazuhiko, Takeuchi Tsutomu

Annals of the Rheumatic Diseases 77 1268 2018年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

Objective: To evaluate the sustained remission and low disease activity after discontinuation of tocilizumab in patients with rheumatoid arthritis who were treated with tocilizumab alone or in combination with methotrexate. Methods: The SURPRISE study was a 2-year, open-label randomised controlled study. Among patients who had been randomised to additional tocilizumab (ADD-ON) or switch to tocilizumab (SWITCH) in the first year, those who achieved remission based on the disease activity score for 28 joints (DAS28-ESR<2.6) discontinued tocilizumab at week 52 and were observed for the following 52 weeks. The endpoint of the second year included tocilizumab-free remission and low disease-Activity rates, functional outcome, radiological outcomes assessed with the modified total Sharp score (mTSS) and safety. The efficacy of reinstituted tocilizumab/methotrexate was also evaluated. Results: A total of 105 patients who achieved remission at week 52 discontinued tocilizumab; 51 in ADD-ON continued methotrexate and 54 in SWITCH received no disease-modifying antirheumatic drugs. Sustained DAS28 low disease-Activity rates were significantly higher in ADD-ON than in SWITCH (55%vs27%, p=0.005). Sustained remission rates at week 104 were 24% for ADD-ON and 14% for SWITCH (p=0.29). Radiological progression was comparable between both groups (mTSS; 0.37vs0.64, p=0.36). The restart of tocilizumab induced remission in all except two patients after 36 weeks, irrespective of concomitant methotrexate. Conclusion: Sustained low disease activity after tocilizumab discontinuation could be maintained with continued methotrexate in more than half of the patients. Retreatment with tocilizumab led to remission in more than 90% of patients. Trial registration number: NCT01120366; Results.

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Clinical practice guideline for Sjögren’s syndrome 2017

Sumida T., Azuma N., Moriyama M., Takahashi H., Asashima H., Honda F., Abe S., Ono Y., Hirota T., Hirata S., Tanaka Y., Shimizu T., Nakamura H., Kawakami A., Sano H., Ogawa Y., Tsubota K., Ryo K., Saito I., Tanaka A., Nakamura S., Takamura E., Tanaka M., Suzuki K., Takeuchi T., Yamakawa N., Mimori T., Ohta A., Nishiyama S., Yoshihara T., Suzuki Y., Kawano M., Tomiita M., Tsuboi H.

Modern Rheumatology （Modern Rheumatology） 28 （ 3 ） 383 - 408 2018年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2018 Japan College of Rheumatology. Published by Informa UK Limited, trading as Taylor & Francis Group. Objectives: The objective of this study is to develop clinical practice guideline (CPG) for Sjögren’s syndrome (SS) based on recently available clinical and therapeutic evidences. Methods: The CPG committee for SS was organized by the Research Team for Autoimmune Diseases, Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW), Japan. The committee completed a systematic review of evidences for several clinical questions and developed CPG for SS 2017 according to the procedure proposed by the Medical Information Network Distribution Service (Minds). The recommendations and their strength were checked by the modified Delphi method. The CPG for SS 2017 has been officially approved by both Japan College of Rheumatology and the Japanese Society for SS. Results: The CPG committee set 38 clinical questions for clinical symptoms, signs, treatment, and management of SS in pediatric, adult and pregnant patients, using the PICO (P: patients, problem, population, I: interventions, C: comparisons, controls, comparators, O: outcomes) format. A summary of evidence, development of recommendation, recommendation, and strength for these 38 clinical questions are presented in the CPG. Conclusion: The CPG for SS 2017 should contribute to improvement and standardization of diagnosis and treatment of SS.

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A Low molecular weight BAFF receptor antagonist inhibits differentiation of human peripheral B cells into plasma blasts/plasma cells in vitro.

Yoshimoto Keiko, Seki Noriyasu, Suzuki Katsuya, Sugahara Kunio, Takeuchi Tsutomu

JOURNAL OF IMMUNOLOGY 200 （ 1 ） 2018年05月

研究論文（学術雑誌）, 査読有り, ISSN 0022-1767

Clinicopathologic investigation of methotrexate-induced lymphoproliferative disorders, with a focus on regression

竹内勤

Leukemia and Lymphoma （Leukemia and Lymphoma） 59 （ 5 ） 1143 - 52 2018年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 10428194

© 2017 Informa UK Limited, trading as Taylor & Francis Group. Although recent accumulative data reveal the clinicopathogenesis of regression in methotrexate-induced lymphoproliferative disorders (MTX-LPDs), the precise understanding including this category remains controversial. In this study, we analyzed 62 patients with MTX-LPD. Forty-three patients showed regression (Reg group), with high rates of Hodgkin lymphoma (HL) and LPD (90 and 88%, respectively). Among the 43 patients of the Reg group, 14 patients (33%) relapsed. The median duration before relapse in the Reg group was 10.6 months. Although the difference of OS between the Reg and Non-Reg groups was not significantly different, relapse-free patients in the Reg group had a superior overall survival (OS). MTX duration had a significant impact on Epstein–Barr virus (EBV) infection (p =.00131). Furthermore, EBV infection was significantly related to clinical manifestations, including spleen invasion, in the regression phenomenon. Some human leukocyte antigens (HLA) alleles might affect MTX-LPD development via EBV infection, although A*2402 and DRB1*0405 might be affected as fundamental factors.

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DURABILITY, MAINTENANCE AND EFFECTS OF DOSE REDUCTION FOLLOWING PROLONGED TREATMENT WITH BARICITINIB

Smolen J., Dougados M., Takeuchi T., Genovese M., Haraoui B., Klar R., Kavanaugh A., Alonso R. B., Dudler J., Taylor P., Nash P., Zerbini C., Durez P., Pum G., Arthanari S., De Leonardis F., van Vollenhoven R.

INTERNAL MEDICINE JOURNAL 48 43 - 43 2018年05月

研究論文（学術雑誌）, 査読有り, ISSN 1444-0903

Efficacy and safety of sirukumab in Japanese patients with active rheumatoid arthritis who were refractory or intolerant to anti-tumor necrosis factor therapy

Tanaka Yoshiya, Takeuchi Tsutomu, Harigai Masayoshi, Yamanaka Hisashi, Nakano Toshikazu, Akagi Koshiro, Ukyo Yoshifumi, Hsu Benjamin

Modern Rheumatology 1 - 8 2018年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objective: To evaluate the efficacy and safety of sirukumab, a human anti-interleukin six monoclonal antibody, in Japanese patients with rheumatoid arthritis who were refractory to anti-tumor necrosis factor therapy. Methods: This subgroup analysis, based on a double-blind, placebo-controlled, 52-week phase 3, global study (SIRROUND-T) assessed the American College of Rheumatology (ACR) 20 response at week 16 (primary endpoint). Secondary endpoints: ACR 50, Disease Activity Score in 28 joints-C reactive protein, Health Assessment Questionnaire-Disability Index and safety were assessed. Results 116/878 patients received sirukumab 50 mg/4 weeks (q4w, n = 35), 100 mg/2 weeks (q2w, n = 44) or placebo (n = 37) subcutaneously. Significantly more patients achieved ACR 20 response at week 16 with sirukumab (50 mg q4w:20 [57.1%]; p < .001, 100 mg q2w:24 [54.5%]; p = .001) versus placebo (7 [18.9%]); consistent significant improvement in secondary endpoints at week 24 and 52 was observed. At week 24, incidence of treatment-emergent adverse events (TEAEs) was numerically higher with sirukumab groups (50 mg q4w:29 [82.9%]; 100 mg q2w:38 [86.4%] versus placebo (28 [75.7%]); however, at week 52, sirukumab combined groups had comparable incidence of TEAEs. Conclusion: Efficacy findings through 52 weeks were comparable between sirukumab doses in Japanese patients and consistent with primary SIRROUND-T study results. No new safety signals were observed.

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Restoration of decreased T helper 1 and CD8+ T cell subsets is associated with regression of lymphoproliferative disorders developed during methotrexate treatment

Saito S., Suzuki K., Yoshimoto K., Kaneko Y., Yamaoka K., Shimizu T., Mori T., Okamoto S., Kameyama K., Amano K., Tamaru J., Tokuhira M., Takeuchi T.

Frontiers in Immunology （Frontiers in Immunology） 9 （ APR ） 621 2018年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1664-3224

© 2018 Saito, Suzuki, Yoshimoto, Kaneko, Yamaoka, Shimizu, Mori, Okamoto, Kameyama, Amano, Tamaru, Tokuhira and Takeuchi. Background: Lymphoproliferative disorder (LPD), including malignant lymphoma, is a relatively rare but life-threatening complication in RA patients under methotrexate (MTX) therapy. Spontaneous regression of LPD after MTX withdrawal is regarded as a distinct characteristic in part of such LPDs. Objective: The present study aimed to investigate the immunological difference in regressive LPD and persistent LPD. Methods: We studied RA patients who developed LPD during MTX administration (n = 35) and clinically matched controls (n = 35). The time of MTX cessation was defined as week 0, and LPD patients were divided into two groups according to LPD status at week 12: regressive group (n = 22) and persistent group (n = 13). Flow cytometric analysis of whole blood samples and serum cytokine assays were conducted for LPD (n = 10) and control patients (n = 10) at weeks 0, 4, and 12. Results: There was a significant decrease in peripheral lymphocytes and the proportion of T helper 1 cells (Th1 cells), effector memory CD8+ T cells (EMCD8+ T) and Epstein-Barr virus (EBV)-specific CD8+ T cells at the time of LPD diagnosis, and a significant increase after MTX cessation was observed in the regressive group but not in the persistent group. The expansion of Th1 cells and EMCD8+ T cells significantly correlated with an increase in serum interferon (IFN)-γ concentration. Conclusion: Changes in Th1 cells, EMCD8+ T cells and EBV-specific CD8+ T cells, which coincided with an increase in IFN-γ, were significantly different between regressive LPD and persistent LPD after MTX cessation.

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Splicing variant of WDFY4 augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis

Kochi Y., Kamatani Y., Kondo Y., Suzuki A., Kawakami E., Hiwa R., Momozawa Y., Fujimoto M., Jinnin M., Tanaka Y., Kanda T., Cooper R., Chinoy H., Rothwell S., Lamb J., Vencovský J., Mann H., Ohmura K., Myouzen K., Ishigaki K., Nakashima R., Hosono Y., Tsuboi H., Kawasumi H., Iwasaki Y., Kajiyama H., Horita T., Ogawa-Momohara M., Takamura A., Tsunoda S., Shimizu J., Fujio K., Amano H., Mimori A., Kawakami A., Umehara H., Takeuchi T., Sano H., Muro Y., Atsumi T., Mimura T., Kawaguchi Y., Mimori T., Takahashi A., Kubo M., Kohsaka H., Sumida T., Yamamoto K.

Annals of the Rheumatic Diseases （Annals of the Rheumatic Diseases） 77 （ 4 ） 602 - 611 2018年04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) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. Objectives Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases in which both genetic and environmental factors play important roles. To identify genetic factors of IIM including polymyositis, dermatomyositis (DM) and clinically amyopathic DM (CADM), we performed the first genome-wide association study for IIM in an Asian population. Methods We genotyped and tested 496 819 single nucleotide polymorphism for association using 576 patients with IIM and 6270 control subjects. We also examined the causal mechanism of disease-associated variants by in silico analyses using publicly available data sets as well as by in in vitro analyses using reporter assays and apoptosis assays. Results We identified a variant in WDFY4 that was significantly associated with CADM (rs7919656; OR=3.87; P=1.5×10 -8). This variant had a cis-splicing quantitative trait locus (QTL) effect for a truncated WDFY4isoform (tr-WDFY4), with higher expression in the risk allele. Transexpression QTL analysis of this variant showed a positive correlation with the expression of NF-ΚB associated genes. Furthermore, we demonstrated that both WDFY4 and tr-WDFY4 interacted with pattern recognition receptors such as TLR3, TLR4, TLR9 and MDA5 and augmented the NF-ΚB activation by these receptors. WDFY4 isoforms also enhanced MDA5-induced apoptosis to a greater extent in the tr-WDFY4-transfected cells. Conclusions As CADM is characterised by the appearance of anti-MDA5 autoantibodies and severe lung inflammation, the WDFY4 variant may play a critical role in the pathogenesis of CADM.

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Adolescent PR3-ANCA-positive hypertrophic pachymeningitis

Matsumoto K., Akiyama M., Kajio N., Otomo K., Suzuki K., Nishina N., Kasuya K., Oishi N., Kameyama K., Takeuchi T.

Medicine (United States) （Medicine (United States)） 97 （ 17 ） 17 2018年04月

研究論文（学術雑誌）, 査読有り, ISSN 0025-7974

© 2018 the Author(s). Published by Wolters Kluwer Health, Inc. Rationale: Hypertrophic pachymeningitis (HP) is an uncommon, life-threatening disease that is seen in elderly patients with antineutrophil cytoplasmic antibody (ANCA) positivity. Proteinase-3 (PR3)-ANCA-positive HP has not been reported in adolescents. Here, we report the first case of adolescent PR3-ANCA-positive HP successfully treated with immunosuppressive therapy. Patient concerns: A 14-year-old female presented with fullness and pain in her right ear unresponsive to antibiotics. Laboratory tests showed an elevated C-reactive protein and PR3-ANCA positivity. Computed tomography and magnetic resonance imaging revealed mastoiditis in the right temporal bone. Surgical biopsy revealed severe fibrosis and prominent inflammatory-cell infiltration. She received prednisolone and methotrexate therapy, and then underwent a right mastoidectomy. Five months later, she developed headache, dysarthria, and multiple cranial nerve palsies. Further imaging revealed enhancement and thickening of the right hemispheric dura. Diagnosis: PR3-ANCA-positive HP. Interventions: She was successfully treated with steroid pulse therapy for 3 days, followed by high doses of prednisolone and intravenous cyclophosphamide. Outcome: The treatment resulted in significant improvement of her symptoms, laboratory data, and radiologic findings. Lessons: PR3-ANCA-positive HP can present not only in the elderly, but also in adolescence, and prompt diagnosis and treatment with immunosuppressive therapy is vital.

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Akiyama M., Takeuchi T.

Drugs and Aging （Drugs and Aging） 35 （ 4 ） 275 - 287 2018年04月

研究論文（学術雑誌）, 査読有り, ISSN 1170229X

© 2018, Springer International Publishing AG, part of Springer Nature. IgG4-related disease is a heterogeneous immune-mediated fibroinflammatory condition that can affect every single organ. This disease is more prevalent in the elderly (the mean age of patients is above 60 years) and the prevalence rate is estimated to be over 4.6 per 100,000 population. Before making a diagnosis, the exclusion of malignancies, lymphoma, anti-neutrophil cytoplasmic antibody-associated vasculitis, multicentric Castleman disease, and other mimickers is crucial for appropriate treatment. Broad management guidelines have been published emphasizing the need for prompt treatment and the use of glucocorticoids as first-line drug therapy for induction of remission. However, the toxic effects of glucocorticoids are problematic because IgG4-related disease is more prevalent in patients above 60 years of age, a population with frequent comorbid conditions and polypharmacy. Immunosuppressants (cyclophosphamide, methotrexate, leflunomide, and tacrolimus) and targeted immunomodulators (rituximab, XmAb5871, and abatacept) are appealing to overcome potential toxic effects of glucocorticoids and as emerging glucocorticoid-sparing and/or maintenance treatments. In this review, we provide an overview of our understanding of the pathophysiology of the disease (T follicular helper cells, CD4+ cytotoxic T cells, plasmablasts, and alternatively activated M2 macrophages) and clinical characteristics, and highlight the potential targets for treatment intervention.

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DURABILITY, MAINTENANCE AND EFFECTS OF DOSE REDUCTION FOLLOWING PROLONGED TREATMENT WITH BARICITINIB

Smolen Josef S., Dougados Maxime, Takeuchi Tsutomu, Genovese Mark C., Haraoui Boulos, Klar Rena, Kavanaugh Arthur, Alonso Ricardo B., Dudler Jean, Taylor Peter C., Nash Peter, Zerbini Cristiano A., Durez Patrick, Pum Georg, Arthanari Subhashini, De Leonardis Francesco, van Vollenhoven Ronald

RHEUMATOLOGY 57 2018年04月

研究論文（学術雑誌）, 査読有り, ISSN 1462-0324

IgG4-Related Disease

Akiyama Mitsuhiro, Takeuchi Tsutomu

Drugs and Aging 35 275 - 287 2018年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1170-229X

IgG4-related disease is a heterogeneous immune-mediated fibroinflammatory condition that can affect every single organ. This disease is more prevalent in the elderly (the mean age of patients is above 60 years) and the prevalence rate is estimated to be over 4.6 per 100,000 population. Before making a diagnosis, the exclusion of malignancies, lymphoma, anti-neutrophil cytoplasmic antibody-associated vasculitis, multicentric Castleman disease, and other mimickers is crucial for appropriate treatment. Broad management guidelines have been published emphasizing the need for prompt treatment and the use of glucocorticoids as first-line drug therapy for induction of remission. However, the toxic effects of glucocorticoids are problematic because IgG4-related disease is more prevalent in patients above 60 years of age, a population with frequent comorbid conditions and polypharmacy. Immunosuppressants (cyclophosphamide, methotrexate, leflunomide, and tacrolimus) and targeted immunomodulators (rituximab, XmAb5871, and abatacept) are appealing to overcome potential toxic effects of glucocorticoids and as emerging glucocorticoid-sparing and/or maintenance treatments. In this review, we provide an overview of our understanding of the pathophysiology of the disease (T follicular helper cells, CD4⁺ cytotoxic T cells, plasmablasts, and alternatively activated M2 macrophages) and clinical characteristics, and highlight the potential targets for treatment intervention.

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Risk factors of relapse following glucocorticoid tapering in IgG4-related disease

竹内勤

Clinical and Experimental Rheumatology （Clinical and Experimental Rheumatology） 36 （ 3 ） S157 - S164 2018年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0392856X

© Copyright CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 2018. Objective. To identify risk factors of relapse in IgG4-related disease (IgG4-RD) during glucocorticoid (GC) tapering. Methods. A total of 27 consecutive patients with IgG4-RD (7 with and 20 without relapse) treated with GC for more than 6 months were enrolled. Baseline characteristics were compared in patients with and without relapse. Longitudinal analysis was also performed. Results. Patients with relapse had significantly higher levels of serum IgG4 (816.0 vs. 346.5 mg/dL, p=0.048) and number of organs involved (5 vs. 3, p=0.008) and lower levels of serum IgA (82 vs. 176 mg/dL, p=0.002) at baseline, compared to patients without relapse. The most useful cut-off value of baseline serum IgG4 to predictive relapse was 813 mg/dl with a sensitivity of 57.1% and a specificity of 95.0%. In longitudinal analysis, serum IgG4 decreased at 6 months after treatment in both groups, but was elevated at relapse in patients with relapse, while remaining low in those without relapse. Conclusion. Higher levels of serum IgG4 at baseline were associated with relapse in IgG4-RD. Re-elevation of serum IgG4 levels during GC treatment reflected disease relapse.

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

Yasuoka Hidekata, Shirai Yuichiro, Tamura Yuichi, Takeuchi Tsutomu, Kuwana Masataka

Circulation Journal 82 （ 2 ） 546 - 554 2018年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1346-9843

Background: The potential efficacy of immunosuppressive (IS) treatment has been reported in patients with pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD), but its positioning in the treatment algorithm remains uncertain. The aim of this study was to identify predictors of favorable responses to first-line IS treatment. Methods and Results: This single-center retrospective study included 30 patients with PAH accompanied by systemic lupus erythematosus (SLE), mixed CTD (MCTD), or primary Sjögren’s syndrome (SS) who received first-line IS treatment alone or in combination with pulmonary vasodilators. When short-term treatment response was defined as an improvement in World Health Organization functional class at 3 months, 16 patients (53%) were short-term responders. Simultaneous diagnosis of PAH and CTD, and the use of immunosuppressants, especially intravenous cyclophosphamide, in addition to glucocorticoids were identified as independent predictors of a short-term response (P=0.004 and 0.0002, respectively). Cumulative rates free of PAH-related death were better in short-term responders than non-responders (P=0.04), and were best in patients with a simultaneous diagnosis of PAH and CTD who were treated initially with a combination of glucocorticoids and immunosuppressants. Conclusions: Patients with a simultaneous diagnosis of PAH and CTD, including SLE, MCTD, and primary SS, should receive intensive IS treatment regimens to achieve better short- and long-term outcomes.

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Tendonitis on the fingers in Behçet’s disease

Matsumoto Kotaro, Kaneko Yuko, Takeuchi Tsutomu

Internal Medicine 57 （ 17 ） 2018年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0918-2918

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Safety, pharmacokinetics, and efficacy of E6011, an antifractalkine monoclonal antibody, in a first-in-patient phase 1/2 study on rheumatoid arthritis

Tanaka Y., Takeuchi T., Umehara H., Nanki T., Yasuda N., Tago F., Kawakubo M., Kitahara Y., Hojo S., Kawano T., Imai T.

Modern Rheumatology （Modern Rheumatology） 28 （ 1 ） 58 - 65 2018年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2017 Japan College of Rheumatology. Objective: Fractalkine (CX3CL1/FKN) is a chemokine that regulates chemotaxis and adhesion of CX3C chemokine receptor 1 (CX3CR1)-expressing inflammatory cells. We conducted the first phase 1/2, open-label, multiple ascending dose study of E6011, a humanized anti-FKN monoclonal antibody, in Japanese rheumatoid arthritis (RA) patients (clinicaltrial.gov identifier: NCT02196558). Methods: Active RA patients with an inadequate response or intolerance to methotrexate or tumor necrosis factor (TNF) inhibitor received E6011 at week 0, 1, 2, and thereafter every 2 weeks for 12 weeks. Results: Twelve, 15, and 10 subjects were enrolled in the 100, 200, and 400 mg cohorts, respectively. No severe adverse events (AEs) or deaths occurred, and no major differences were observed in the incidence or severity of AEs across the cohorts. Serum E6011 concentrations increased dose dependently. American College of Rheumatology (ACR) 20, 50, and 70 responses at week 12 were 75.0%, 33.3%, and 8.3% in the 100 mg cohort; 66.7%, 20.0%, and 13.3% in the 200 mg cohort; and 60.0%, 30.0%, and 20.0% in the 400 mg cohort, respectively. Conclusions: E6011 appeared to be safe and well tolerated in RA patients during this 12-week treatment period, suggesting that E6011 has an effective clinical response in active RA patients.

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Safety and effectiveness of tacrolimus add-on therapy for rheumatoid arthritis patients without an adequate response to biological disease-modifying anti-rheumatic drugs (DMARDs): Post-marketing surveillance in Japan

Takeuchi T., Ishida K., Shiraki K., Yoshiyasu T.

Modern Rheumatology （Modern Rheumatology） 28 （ 1 ） 48 - 57 2018年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2017 Japan College of Rheumatology. Published by Informa UK Limited, trading as Taylor & Francis Group. Objectives: Post-marketing surveillance (PMS) was conducted to assess the safety and effectiveness of tacrolimus (TAC) add-on therapy for patients with rheumatoid arthritis (RA) and an inadequate response to biological disease-modifying anti-rheumatic drugs (DMARDs). Methods: Patients with RA from 180 medical sites across Japan were registered centrally with an electronic investigation system. The observational period was 24 weeks from the first day of TAC administration concomitantly with biological DMARDs. Results: Safety and effectiveness populations included 624 and 566 patients, respectively. Patients were predominantly female (81.1%), with a mean age of 61.9 years. Overall, 125 adverse drug reactions (ADRs) occurred in 94 patients (15.1%), and 15 serious ADRs occurred in 11 patients (1.8%). These incidences were lower compared with previously reported incidences after TAC treatment in PMS, and all of the observed ADRs were already known. A statistically significant improvement was observed in the primary effectiveness variable of Simplified Disease Activity Index after TAC treatment; 62.7% of patients achieved remission or low disease activity at week 24. Conclusions: TAC is well tolerated and effective when used as an add-on to biological DMARDs in Japanese patients with RA who do not achieve an adequate response to biological DMARDs in a real-world clinical setting.

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Post-marketing surveillance study of the long-term use of mizoribine for the treatment of lupus nephritis: 2-Year results

Takeuchi T., Okada K., Yoshida H., Yagi N.

Modern Rheumatology （Modern Rheumatology） 28 （ 1 ） 85 - 94 2018年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2017 Japan College of Rheumatology. Published by Informa UK Limited, trading as Taylor & Francis Group. Objectives: To understand the status of mizoribine use in patients with lupus nephritis (LN) and to collect safety- and efficacy-related data on 2-year treatment with mizoribine. Methods: A continuous survey was conducted between March 2010 and July 2015. Results: The analysis set included 559 patients (mean age 39.5 years, females 82.6%, mean duration of systemic lupus erythematosus (SLE) 8.4 years, mean duration of LN 5.9 years). Renal function was satisfactory for 6 months, but worsened from 12 months, with significant worsening at 24 months. By the ACR 2006 remission criteria (eGFR >60), at 24 months, 26.5% of patients achieved complete remission, and 63.3% achieved complete or partial remission. The urine protein to creatinine ratio decreased significantly. The SLE Disease Activity Index 2000 score decreased significantly at 12 and 24 months. Overall, 98 (17.5%) patients experienced 124 adverse drug reactions (ADRs); 3.6% experienced serious ADRs. Mizoribine was used with a steroid in 99.3% and an immunosuppressant in 51.2%; tacrolimus was used in 43.8%. The oral steroid dosage decreased from baseline to 24 months. The incidence of ADRs was not significantly different with concomitant tacrolimus use. Conclusions: The results suggest that long-term mizoribine is safe and effective, even when used with tacrolimus.

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Economic impact of adalimumab treatment in Japanese patients with rheumatoid arthritis from the adalimumab non-interventional trial for up-verified effects and utility (ANOUVEAU) study

Tanaka Y., Yamazaki K., Nakajima R., Komatsu S., Igarashi A., Tango T., Takeuchi T.

Modern Rheumatology （Modern Rheumatology） 28 （ 1 ） 39 - 47 2018年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2017 Japan College of Rheumatology. Objectives: The objective of this study is to evaluate the economic impact of adalimumab (ADA) on Japanese rheumatoid arthritis (RA) patients. Methods: ANOUVEAU was a 48-week multicenter, prospective, observational, single-cohort study. Work-related outcomes including absenteeism, presenteeism, overall work impairment (OWI), and activity impairment (AI) were evaluated using the RA-related work productivity and activity impairment (WPAI/RA). The amount of productivity loss was estimated via multiplication of absenteeism, presenteeism and OWI by the national average occupational wage for paid worker (PW) and part time worker (PTW), and via multiplication of AI by the estimated wage for domestic work for home maker (HM). Results: In this analysis, 1196 patients were included. At week 48, measures of productivity loss due to absenteeism, presenteeism, OWI, and AI were significantly improved by administrating ADA to RA patients in all employment types (PW, PTW, and HM), compared to baseline (p <.01). Productivity loss of Japanese society by RA disease was estimated to be $9.80 billion. The annual decrease in productivity loss through ADA administration to Japanese RA patients was estimated to be $3.76 billion. Conclusions: The socioeconomic burden of RA is high, but ADA treatment may reduce productivity loss related to RA.

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Biomarkers as a treatment guide in rheumatoid arthritis

Takeuchi T.

Clinical Immunology （Clinical Immunology） 186 59 - 62 2018年01月

研究論文（学術雑誌）, 査読有り, ISSN 15216616

© 2017 Elsevier Inc. It is anticipated that biomarkers support rheumatologists to judge a group of patients that can improve the diagnosis and prognosis, and further facilitate appropriate and precise treatment with targeted therapy. In particular, biomarkers for predicting and monitoring response to biological disease modifying anti-rheumatic drugs (DMARDs) are demanding. Given the mechanism action of biological DMARDs is much more simple than the conventional synthetic DMARDs, a variety of approaches to find such biomarkers has been taken recent years. In this article, I will summarize the background for biomarker research and introduce recent topics in the research and the possible clinical applications of biomarkers to guide treatment in rheumatoid arthritis (RA).

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[Diagnosis and treatment of rheumatoid arthritis:toward the best practice. Towards precision medicine in rheumatoid arthritis.]

Suzuki K, Takeuchi T

Clinical calcium 28 （ 5 ） 626 - 629 2018年

研究論文（学術雑誌）, 査読有り, ISSN 0917-5857

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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 Sjogren'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 36 （ 3 ） S157 - S164 2018年

研究論文（学術雑誌）, 査読有り, ISSN 0392-856X

Safety profile of baricitinib for the treatment of rheumatoid arthritis up to 5.5 years: an updated integrated safety analysis

Genovese M., Smolen J., Takeuchi T., Hyslop D., Macias W., Rooney T., Chen L., Dickson C., Riddle J., Cardillo T., Ishii T., Winthrop K., Larsson E.

SCANDINAVIAN JOURNAL OF RHEUMATOLOGY 47 35 - 35 2018年

研究論文（学術雑誌）, 査読有り, ISSN 0300-9742

Clinical and immunological features of anti-centromere antibody-positive primary Sjogren's syndrome

Tsukamoto Masako, Suzuki Katsuya, Takeuchi Tsutomu

CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 36 （ 3 ） S282 - S282 2018年

研究論文（学術雑誌）, 査読有り, ISSN 0392-856X

Increased circulating CD14(bright)CD16(+) intermediate monocytes are regulated by TNF-alpha and IL-6 axis in accordance with disease activity in patients with rheumatoid arthritis

Tsukamoto Masako, Suzuki Katsuya, Seta Noriyuki, Takeuchi Tsutomu

CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 36 （ 4 ） 540 - 544 2018年

研究論文（学術雑誌）, 査読有り, ISSN 0392-856X

Factors predicting the therapeutic response to methotrexate in Japanese patients with rheumatoid arthritis: A hospital-based cohort study

Hakamata J., Kaneko Y., Shimizu M., Yamaoka K., Maruyama J., Takeuchi T., Mochizuki M., Hashiguchi M.

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

研究論文（学術雑誌）, 査読有り, ISSN 09186158

© 2018 The Pharmaceutical Society of Japan. 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.

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Discovery of drug candidates for primary Sjogren's syndrome that target a BAFF receptor

Yoshimoto Keiko, Suzuki Katsuya, Seta Noriyasu, Sugahara Kunio, Chiba Kenji, Takeuchi Tsutomu

CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 36 （ 3 ） S283 - S283 2018年

研究論文（学術雑誌）, 査読有り, ISSN 0392-856X

Clinical efficacy, radiographic, and safety results of golimumab monotherapy in Japanese patients with active rheumatoid arthritis despite prior therapy with disease-modifying antirheumatic drugs: Final results of the GO-MONO trial through week 120

竹内勤

Modern Rheumatology （Modern Rheumatology） 28 （ 5 ） 770 - 779 2017年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 14397595

© 2017, © 2017 Japan College of Rheumatology. Published by Informa UK Limited, trading as Taylor & Francis Group. Objective: Evaluate the safety and efficacy of golimumab through week 120 in Japanese patients with active rheumatoid arthritis (RA) previously treated with DMARDs. Methods: Japanese patients with active RA despite prior DMARDs were randomized to placebo (Group 1, n = 105), golimumab 50 mg (Group 2, n = 101), or golimumab 100 mg (Group 3, n = 102). At week 16, Group 1 patients crossed over to golimumab 50mg; after week 52, a one-time golimumab dose reduction from 100 to 50 mg was permitted. Assessments included ACR20/50/70 responses and good/moderate DAS28-ESR responses. Radiographic progression was assessed with the van der Heijde-modified Sharp (vdH-S) score. Safety and efficacy were assessed through week 120. Results: ACR20 response rates at week 52 in Group 1, Group 2, and Group 3 were 70.6%, 71.4%, and 81.9%, respectively, and maintained through week 104 (87.2%, 85.1%, 88.9%, respectively) and week 120 (86.1%, 87.0%, 89.5%, respectively). Similar trends were observed for ACR50, ACR 70, and DAS28-ESR. Median change in total vdH-S at weeks 52, 104, and 120 ranged from 0.0 to 1.5 across treatment groups. Through week 120, 93.8%/97.1% had an AE with golimumab 50 mg/100 mg, respectively, and 19.7%/11.8% had an SAE. Infections were the most common AE. Conclusion: Clinical response to golimumab 50 mg and 100 mg was maintained over 2 years in Japanese patients with active RA despite prior DMARDs.

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Serum soluble interleukin-2 receptor is a useful biomarker for disease activity in IgG4-related disease and primary Sjogren’s syndrome

竹内勤

Clinical Experimental Rheumatology 2017年12月

研究論文（学術雑誌）, 共著, 査読有り

Polymyositis with elevated serum IgG4 levels and abundant IgG4 + plasma cell infiltration

Anan R., Akiyama M., Kaneko Y., Kikuchi J., Suzuki K., Matsubara S., Takeuchi T.

Medicine (United States) （Medicine (United States)） 96 （ 48 ） 2017年12月

研究論文（学術雑誌）, 査読有り, ISSN 00257974

Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc. Introduction: Polymyositis (PM) is a type of autoimmune, inflammatory myopathy. IgG4-related disease (IgG4-RD) is a recently recognized disease entity characterized by elevated serum IgG4 levels and IgG4 + plasma-cell infiltration of various organs. However, several reports have described cases of other diseases that present with those features, suggesting the importance of careful differential diagnosis. Herein, we report the first case of PM with elevated serum IgG4 levels and IgG4 + plasma cells in the muscles, mimicking IgG4-RD. A 73-year-old woman visited our hospital because of proximal muscle weakness of both thighs. Her blood test showed high levels of serum creatinine kinase, aldolase, and IgG4. Magnetic resonance imaging of the thighs showed muscle edema. Needle electromyography showed findings typical of myositis. Histological analysis of her left quadriceps revealed infiltration of IgG4 + plasma cells as well as CD8 + T cells. Scattered necrotic and regenerating muscle fibers with no specific findings for IgG4-RD (storiform fibrosis and obliterative phlebitis) were typical for PM. We diagnosed her condition as PM and treated her with 40 mg/day of prednisolone that decreased levels of muscle enzymes and improved muscle weakness. Conclusion: Our case indicated that PM could present with high serum IgG4 levels and IgG4 + plasma-cell infiltration, mimicking IgG4-RD. Although the mechanism of IgG4 elevation in such PM is unclear, our case highlights the necessity to recognize that high serum IgG4 levels and IgG4 + plasma-cell infiltration in organs are not specific for IgG4-RD.

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Genome-wide Association Study of Idiopathic Osteonecrosis of the Femoral Head

Sakamoto Y., Yamamoto T., Sugano N., Takahashi D., Watanabe T., Atsumi T., Nakamura J., Hasegawa Y., Akashi K., Narita I., Miyamoto T., Takeuchi T., Ikari K., Amano K., Fujie A., Kubo T., Tada Y., Kaneuji A., Nakamura H., Miyamura T., Kabata T., Yamaji K., Okawa T., Sudo A., Ohzono K., Tanaka Y., Yasunaga Y., Matsuda S., Imai Y., Nakashima Y., Motomura G., Ikemura S., Yamaguchi R., Karasuyama K., Sonoda K., Nishii T., Sakai T., Takao M., Irie T., Asano T., Iwasaki N., Atsumi T., Tamaoki S., Nakanishi R., Tanabe S., Kishida S., Hagiwara S., Seki T., Tsukamoto H., Niiro H., Arinobu Y., Akahoshi M., Mitoma H., Ayano M., Kuroda T., Toyama Y., Funayama A., Hanaoka H., Yamaoka K., Kawaguchi Y., Yamanaka H., Hosozawa T., Momohara S., Chino K., Fujioka M., Ueshima K., Ishida M., Saito M., Hayashi S., Ikegami A., Ichiseki T., Mizokawa S., Ohta Y., Kajino Y., Sekiya F., Higuchi F., Hasegawa M., Miyamoto N., Miyazaki S., Yamaguchi T., Ando W., Saito K., Nakano K., Kuroda Y., Yamasaki T., Akiyama M., Kubo M., Kamatani Y., Iwamoto Y., Ikegawa S.

Scientific Reports （Scientific Reports） 7 （ 1 ） 2017年12月

研究論文（学術雑誌）, 査読有り

© 2017 The Author(s). Idiopathic osteonecrosis of the femoral head (IONFH) is an ischemic disorder that causes bone necrosis of the femoral head, resulting in hip joint dysfunction. IONFH is a polygenic disease and steroid and alcohol have already known to increase its risk; however, the mechanism of IONFH remains to be elucidated. We performed a genome-wide association study using ~60,000 subjects and found two novel loci on chromosome 20q12 and 12q24. Big data analyses identified LINC01370 as a candidate susceptibility gene in the 20q12 locus. Stratified analysis by IONFH risk factors suggested that the 12q24 locus was associated with IONFH through drinking capacity. Our findings would shed new light on pathophysiology of IONFH.

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Remission induction by Raising the dose of Remicade in RA (RRRR) study: Rationale and study protocol for a randomized controlled trial comparing for sustained clinical remission after discontinuation of infliximab in patients with rheumatoid arthritis

Oba K., Horie N., Sato N., Saito K., Takeuchi T., Mimori T., Miyasaka N., Koike T., Tanaka Y.

Contemporary Clinical Trials Communications （Contemporary Clinical Trials Communications） 8 49 - 54 2017年12月

研究論文（学術雑誌）, 査読有り, ISSN 24518654

© 2017 The Authors Infliximab, an inhibitor of TNF-α, is one of the most widely used biological disease-modifying antirheumatic drugs. Recent studies indicated that baseline serum TNF-α could be considered as a key indicator for optimal dosing of infliximab for RA treatment to achieve the clinical response and its sustained remission. The Remission induction by Raising the dose of Remicade in RA (RRRR) study is an open-label, parallel group, multicenter randomized controlled trial to compare the proportions of clinical remission based on the simplified disease activity index (SDAI) after 1 year of treatment and its sustained remission rate after another 1 year between the investigational treatment strategy (for which the dose of infliximab was chosen based on the baseline serum TNF) and the standard strategy of 3 mg/kg per 8 weeks of infliximab administration in infliximab-naïve patients with RA showing an inadequate response to MTX. The primary endpoint is the proportion of patients who kept discontinuation of infliximab 1 year after discontinued infliximab at the time of 54 weeks after the first administration of infliximab. The secondary endpoints are the proportion of clinical remission based on SDAI and changes in SDAI from baseline at each time point, other clinical parameters, quality of life measures and adverse events. Target sample size of randomized patients is 400 patients in total. The main results of the RRRR study are expected to be published at the end of 2017.

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Efficacy and safety of baricitinib in Japanese patients with rheumatoid arthritis: Subgroup analysis of four multinational phase 3 randomized trials

竹内勤

Modern Rheumatology 2017年11月

研究論文（学術雑誌）, 共著, 査読有り

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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Proteinuria selectivity index as a prognostic biomarker in lupus nephritis

Hasegawa T., Suzuki K., Kaneko Y., Takeuchi T.

Lupus （Lupus） 26 （ 6 ） 656 - 660 2017年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0961-2033

© SAGE Publications. Objectives The selectivity index has been proposed in predicting the response to immunosuppressive therapy in nephrotic syndrome and other primary kidney disorders. The aim of this study was to elucidate the predictive value of the selectivity index for the treatment response and renal outcome in patients with lupus nephritis. Methods Forty-four patients with lupus nephritis with selectivity index available at the time of renal biopsy were divided into two groups according to the cut-off value of the selectivity index determined by a receiver operating characteristics curve to differentiate treatment responders from non-responders. The baseline characteristics, overall response rate and renal functional outcome were studied retrospectively, and compared between the two groups. Prognostic factors for achieving remission were identified. Results The cut-off value of the selectivity index was 0.167. The low selectivity index (<0.167) and the high selectivity index (≥0.167) group included 24 and 20 patients, respectively. The overall response rate was significantly higher (88% vs. 50%, P = 0.007) and the rate of progression to end-stage renal disease was lower in the low selectivity index group (0% vs. 15%, P = 0.049). More patients in the high selectivity index group had chronic lesions on renal biopsy (P = 0.002). The selectivity index was the prognostic factor for achieving overall response based on a multivariate analysis (P = 0.020). Conclusions A selectivity index ≥0.167 was a strong predictor for a poor treatment response and the presence of chronic lesions on renal biopsy. Further exploration with a larger cohort and longer follow-up period is warranted.

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Utility of dose frequency adjustment in tocilizumab administration for rheumatoid arthritis

Saito S., Kaneko Y., Izumi K., Takeuchi T.

Journal of Rheumatology （Journal of Rheumatology） 44 （ 5 ） 553 - 557 2017年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

© Copyright 2017. All rights reserved. Objective. To assess the utility of dose frequency adjustment of tocilizumab (TCZ) in rheumatoid arthritis (RA). Methods. Patients who received TCZ at 3-week (n = 24) or 5-week (n = 61) interval were evaluated. Results. Disease Activity Score at 28 joints based on erythrocyte sedimentation rate in the 3-week group significantly improved after 3 administrations at 3-week intervals (from 4.2 to 2.7, p = 0.001). Forty-five of the patients in the 5-week group (74%) successfully continued 5-week interval administration without disease exacerbation. Lower C-reactive protein level at TCZ initiation and shorter duration to remission achievement were key to successful dose frequency reduction. Conclusion. Adjusting the dose frequency of intravenous TCZ is a useful strategy.

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Survey on attitudes regarding EULAR recommendations for the role of nurses involved in medical care of patients with chronic inflammatory arthritis in Japan

Fusama M., Nakahara H., van Eijk-Hustings Y., Oliver S., Takeuchi T.

Modern Rheumatology （Modern Rheumatology） 27 （ 5 ） 886 - 893 2017年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2017 Japan College of Rheumatology. Objective: We seek to evaluate the opinions of nurses and doctors in Japan regarding EULAR recommendations for nurses’ roles in the management of chronic inflammatory arthritis. Methods: This is a cross-sectional survey within Japan. We randomly selected nurses and doctors engaged in consultation of patients with rheumatoid arthritis (RA) and assessed their agreement and opinions on the feasibility of implementing EULAR recommendations, including potential barriers. Results: 431 nurses and 128 doctors completed the questionnaire. For both nurses and doctors, levels of feasibility showed statistically significant lower results compared with those of agreement for all items. When compared between nurses and doctors, agreement showed no statistically significant differences, while nurses’ answers were statistically significant lower for feasibility. Insufficient time, staff and knowledge, lack of established procedures and facilities, and lack of an education system for nurses were cited as barriers to the feasibility of implementing EULAR recommendations. Conclusions: This is the first survey within Japan evaluating opinions regarding EULAR recommendations for nurses’ roles. We found that while agreement was high, feasibility was generally believed to be low. We recommend further research and collaboration between medical professionals in order to implement these recommendations in Japan.

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Pulmonary cryptococcosis developed from a nodule after treatment with infliximab for arthritis associated with ulcerative colitis

Asakura Takanori, Arai Daisuke, Ishii Makoto, Takei Hiroshi, Sugiura Hiroaki, Takeuchi Tsutomu, Betsuyaku Tomoko

Annals of the American Thoracic Society 14 （ 4 ） 603 - 605 2017年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2325-6621

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Comparison of performance of the 2016 ACR-EULAR classification criteria for primary Sjögren's syndrome with other sets of criteria in Japanese patients

Tsuboi H., Hagiwara S., Asashima H., Takahashi H., Hirota T., Noma H., Umehara H., Kawakami A., Nakamura H., Sano H., Tsubota K., Ogawa Y., Takamura E., Saito I., Inoue H., Nakamura S., Moriyama M., Takeuchi T., Tanaka Y., Hirata S., Mimori T., Matsumoto I., Sumida T.

Annals of the Rheumatic Diseases （Annals of the Rheumatic Diseases） 76 （ 8 ） 960 - 977 2017年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00034967

© 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/. Objectives To compare the performance of the new 2016 American College of Rheumatology (ACR)-European League Against Rheumatism (EULAR) classification criteria for primary Sjögren's syndrome (SS) with 1999 revised Japanese Ministry of Health criteria for diagnosis of SS (JPN), 2002 American-European Consensus Group classification criteria for SS (AECG) and 2012 ACR classification criteria for SS (ACR) in Japanese patients. Methods The study subjects were 499 patients with primary SS (pSS) or suspected pSS who were followed up in June 2012 at 10 hospitals in Japan. All patients had been assessed for all four criteria of JPN (pathology, oral, ocular, anti-SS-A/SS-B antibodies). The clinical diagnosis by the physician in charge was set as the € gold standard'. Results pSS was diagnosed in 302 patients and ruled out in 197 patients by the physician in charge. The sensitivity of the ACR-EULAR criteria in the diagnosis of pSS (95.4%) was higher than those of the JPN, AECG and ACR (82.1%, 89.4% and 79.1%, respectively), while the specificity of the ACR-EULAR (72.1%) was lower than those of the three sets (90.9%, 84.3% and 84.8%, respectively). The differences of sensitivities and specificities between the ACR-EULAR and other three sets of criteria were statistically significant (p<0.001). Eight out of 302 patients with pSS and 11 cases out of 197 non-pSS cases satisfied only the ACR-EULAR criteria, compared with none of the other three sets. Conclusions The ACR-EULAR criteria had significantly higher sensitivity and lower specificity in diagnosis of pSS, compared with the currently available three sets of criteria.

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Low disease activity for up to 3 years after adalimumab discontinuation in patients with early rheumatoid arthritis: 2-year results of the HOPEFUL-3 Study

Tanaka Y., Yamanaka H., Ishiguro N., Miyasaka N., Kawana K., Kimura J., Agata N., Takeuchi T.

Arthritis Research and Therapy （Arthritis Research and Therapy） 19 （ 1 ） 56 2017年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1478-6354

© 2017 The Author(s). Background: This study was conducted to evaluate the feasibility of long-term adalimumab (ADA) discontinuation after achievement of low disease activity (LDA) in Japanese patients with early rheumatoid arthritis (RA) and to identify predictors of LDA maintenance. Methods: In the HOPEFUL-1 study, patients received initial therapy with either ADA plus methotrexate (MTX; intensive therapy) or MTX alone (standard therapy) for 26 weeks, followed by ADA + MTX for 26 weeks. In the HOPEFUL-2 study, patients received ADA + MTX (ADA continuation) or MTX alone (ADA discontinuation) for 52 weeks. HOPEFUL-3 was an observational study that enrolled patients who had completed HOPEFUL-2; these patients were followed for an additional 104 weeks. Results: Of the 172 patients enrolled in the HOPEFUL-3 study, 135 (ADA continuation, n = 61; ADA discontinuation, n = 74) with 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) values at both week 52 (start of HOPEFUL-2) and week 208 (end of HOPEFUL-3) were included in the effectiveness analysis. At week 208, 58 (95.1%) of 61 patients and 59 (79.7%) of 74 patients who continued or discontinued ADA, respectively, had LDA (DAS28-CRP <3.2). Initial intensive therapy was associated with a better outcome than standard therapy in terms of change in modified total Sharp score from week 0 to week 208, which was ≤0.5 (64% vs. 30%). The incidence of adverse events was significantly lower in the ADA discontinuation group than in the ADA continuation group (9.7% vs. 32.9%; p < 0.001). Conclusions: Approximately 80% of patients who discontinued ADA for 3 years after achieving LDA with ADA + MTX were still in LDA, with a lower incidence of adverse events than patients who continued ADA. Trial registration: ClinicalTrials.gov identifier: NCT01346501. Registered 29 April 2011.

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Baricitinib, Methotrexate, or Combination in Patients With Rheumatoid Arthritis and No or Limited Prior Disease-Modifying Antirheumatic Drug Treatment

Fleischmann R., Schiff M., van der Heijde D., Ramos-Remus C., Spindler A., Stanislav M., Zerbini C., Gurbuz S., Dickson C., de Bono S., Schlichting D., Beattie S., Kuo W., Rooney T., Macias W., Takeuchi T.

Arthritis and Rheumatology （Arthritis and Rheumatology） 69 （ 3 ） 506 - 517 2017年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2326-5191

© 2016 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology. Objective: We undertook this phase III study to evaluate baricitinib, an orally administered JAK-1/JAK-2 inhibitor, as monotherapy or combined with methotrexate (MTX) compared to MTX monotherapy in patients with active rheumatoid arthritis (RA) who had received no or minimal conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and who were naive to biologic DMARDs. Methods: A total of 588 patients were randomized 4:3:4 to receive MTX monotherapy (once weekly), baricitinib monotherapy (4 mg once daily), or the combination of baricitinib and MTX for 52 weeks. The primary end point assessment was a noninferiority comparison of baricitinib monotherapy to MTX monotherapy based on the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 24. Results: The study met its primary objective. Moreover, baricitinib monotherapy was found to be superior to MTX monotherapy at week 24, with a higher ACR20 response rate (77% versus 62%; P ≤ 0.01). Similar results were observed for combination therapy. Compared to MTX monotherapy, significant improvements in disease activity and physical function were observed for both baricitinib groups as early as week 1. Radiographic progression was reduced in both baricitinib groups compared to MTX monotherapy; the difference was statistically significant for baricitinib plus MTX. The rates of serious adverse events (AEs) were similar across treatment groups, while rates of some treatment-emergent AEs, including infections, were increased with baricitinib plus MTX. Three deaths were reported, all occurring in the MTX monotherapy group. Malignancies, including nonmelanoma skin cancer, were reported in 1 patient receiving MTX monotherapy, 1 receiving baricitinib monotherapy, and 4 receiving baricitinib plus MTX. Conclusion: Baricitinib alone or in combination with MTX demonstrated superior efficacy with acceptable safety compared to MTX monotherapy as initial therapy for patients with active RA.

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CD14brightCD16+ intermediate monocytes are induced by interleukin-10 and positively correlate with disease activity in rheumatoid arthritis

Tsukamoto M., Seta N., Yoshimoto K., Suzuki K., Yamaoka K., Takeuchi T.

Arthritis Research and Therapy （Arthritis Research and Therapy） 19 （ 1 ） 28 2017年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1478-6354

© 2017 The Author(s). Background: Three different subsets of circulating human monocytes, CD14brightCD16- (classical), CD14brightCD16+ (intermediate), and CD14dimCD16+ (non-classical) have been recently identified. It has been reported that CD14brightCD16+ monocytes are increased in rheumatoid arthritis (RA). However, the role of each monocyte subset in the pathogenesis of RA is still unclear. The purpose of this study was to investigate the association of CD14brightCD16+ monocytes with RA. Methods: The study enrolled 35 patients with RA and 14 healthy volunteers. The three subsets of peripheral blood monocytes were analyzed by flow cytometry. Serum cytokines were measured at baseline in patients with RA and in healthy volunteers. CD14brightCD16- monocytes were isolated and cultured in vitro with different cytokines for 14 hours, and CD16 induction was assessed. Results: The proportion of CD14brightCD16+ monocytes, and serum interleukin (IL)-6, IL-8, and IL-10 were increased in patients with RA compared to healthy controls. The proportion of CD14brightCD16+ monocytes correlated with the disease activity of RA positively, whereas the proportion of CD14brightCD16- monocytes correlated negatively. When isolated CD14brightCD16- monocytes were stimulated with IL-6, IL-8, and IL-10, the only cytokine that significantly induced CD16 expression on the cells was IL-10. Conclusions: The proportion of CD16brightCD14+ monocytes was positively correlated with RA disease activity. The expression of CD16 in monocytes was induced by IL-10 but not IL-6, and IL-8 was enhanced in the sera of patients with RA. Our results suggest that CD16brightCD14+ monocytes are involved in the pathogenesis of RA and that IL-10 is a key cytokine that regulates CD16 expression in monocytes.

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Clinical benefit of 1-year certolizumab pegol (CZP) add-on therapy to methotrexate treatment in patients with early rheumatoid arthritis was observed following CZP discontinuation: 2-year results of the C-OPERA study, a phase III randomised trial

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

Annals of the Rheumatic Diseases （Annals of the Rheumatic Diseases） 76 （ 8 ） 1348 - 1356 2017年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

© 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/. Objectives To investigate the clinical impact of 1-year certolizumab pegol (CZP) therapy added to the first year of 2-year methotrexate (MTX) therapy, compared with 2-year therapy with MTX alone. Methods MTX-naïve patients with early rheumatoid arthritis (RA) with poor prognostic factors were eligible to enter Certolizumab-Optimal Prevention of joint damage for Early RA (C-OPERA), a multicentre, randomised, controlled study, which consisted of a 52-week double-blind (DB) period and subsequent 52-week post treatment (PT) period. Patients were randomised to optimised MTX+CZP (n=159) or optimised MTX+placebo (PBO; n=157). Following the DB period, patients entered the PT period, receiving MTX alone (CZP+MTX→MTX; n=108, PBO+MTX→MTX; n=71). Patients who flared could receive rescue treatment with open-label CZP. Results 34 CZP+MTX→MTX patients and 14 PBO+MTX→MTX patients discontinued during the PT period. From week 52 through week 104, significant inhibition of total modified total Sharp score progression was observed for CZP+MTX versus PBO+MTX (week 104: 84.2% vs 67.5% (p<0.001)). Remission rates decreased after CZP discontinuation; however, higher rates were maintained through week 104 in CZP+MTX→MTX versus PBO+MTX→MTX (41.5% vs 29.3% (p=0.026), 34.6% vs 24.2% (p=0.049) and 41.5% vs 33.1% (p=0.132) at week 104 in SDAI, Boolean and DAS28(erythrocyte sedimentation rate) remission. CZP retreated patients due to flare (n=28) showed rapid clinical improvement. The incidence of overall adverse events was similar between groups. Conclusions In MTX-naïve patients with early RA with poor prognostic factors, an initial 1 year of add-on CZP to 2-year optimised MTX therapy brings radiographic and clinical benefit through 2€...years, even after stopping CZP. Trial registration number NCT01451203.

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Impact of Adalimumab on Work Productivity and Activity Impairment in Japanese Patients with Rheumatoid Arthritis: Large-Scale, Prospective, Single-Cohort ANOUVEAU Study

Takeuchi T., Nakajima R., Komatsu S., Yamazaki K., Nakamura T., Agata N., Igarashi A., Tango T., Tanaka Y.

Advances in Therapy （Advances in Therapy） 34 （ 3 ） 686 - 702 2017年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0741-238X

© 2017, The Author(s). Introduction: The Adalimumab Non-interventional Trial for Up-verified Effects and Utility (ANOUVEAU) was a large-scale, multicenter, prospective, observational, single-cohort study that evaluated the effects of adalimumab (ADA) on rheumatoid arthritis (RA)-related work productivity and activity impairment (RA-related WPAI) and disease activity in routine rheumatology care in Japan. Methods: Patients with RA were categorized as paid workers (PWs, ≥35 h/week), part-time workers (PTWs, <35 h/week), or homemakers (HMs, unemployed) and were administered the WPAI for RA (WPAI/RA) questionnaire. All patients who received ADA were followed for 48 weeks to evaluate safety and effectiveness. Results: Of the 1808 patients analyzed, 825, 243, and 740 patients were PWs, PTWs, and HMs, respectively. WPAI/RA domain scores significantly improved at weeks 12, 24, and 48 in all groups, with maximum improvement observed for PWs (p < 0.05). Additionally, remission rates (according to Disease Activity Score 28, erythrocyte sedimentation rate, Simplified Disease Activity Index, or Health Assessment Questionnaire-Disability Index scores) and EuroQol 5-Dimension 3-Level scores significantly increased from baseline to 48 weeks in all groups (p < 0.0001). Analysis of patient subgroups revealed better WPAI/RA outcomes for patients who were biologic-naïve, treated with concomitant methotrexate, or with RA duration of ≤2 years (p < 0.05). The rate of serious adverse events over 48 weeks of ADA treatment was 5.23%. Conclusions: Treatment with ADA provided sustained improvement in WPAI and had an acceptable safety profile in patients with RA. Funding: AbbVie GK and Eisai Co., Ltd. Trial Registration: ClinicalTrials.gov identifier, NCT01346488.

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Suppression of infliximab antibody levels by azathioprine in patients with rheumatoid arthritis

Aomori T., Tsuchiya A., Suzuki S., Jibiki A., Otsuka N., Ishioka E., Kaneko Y., Takeuchi T., Nakamura T.

Pharmazie （Pharmazie） 72 （ 2 ） 95 - 97 2017年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0031-7144

© 2017, Govi-Verlag Pharmazeutischer Verlag GmbH. All rights reserved. In rheumatoid arthritis (RA) treatment, the concomitant use of methotrexate has been shown to reduce the incidence of antibodies to infliximab (ATI), on the other hand, it is unclear whether azathioprine can reduce ATI production. We enrolled a total of 10 Japanese adult patients with RA who were treated with infliximab concomitantly with methotrexate or azathioprine. Serum concentrations of infliximab and ATI of these patients were measured. The mean serum infliximab concentrations was 1.6±1.3 μg/ml in patients with methotrexate and 1.0±0.5 μg/ml in patients with azathioprine. Serum ATI concentrations were below the limit of quantitation in 4 of 5 patients in each group. The results from the present study suggest that azathioprine suppresses ATI production.

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Association of erythrocyte methotrexate-polyglutamate levels with the efficacy and hepatotoxicity of methotrexate in patients with rheumatoid arthritis: A 76-week prospective study

Takahashi C., Kaneko Y., Okano Y., Taguchi H., Oshima H., Izumi K., Yamaoka K., Takeuchi T.

RMD Open （RMD Open） 3 （ 1 ） e000363 2017年01月

研究論文（学術雑誌）, 共著, 査読有り

© Published by the BMJ Publishing Group Limited. Objective: To assess the utility of erythrocyte methotrexate-polyglutamate (MTX-PG) concentrations in determining the safety and efficacy of MTX in patients with rheumatoid arthritis (RA). Methods: 79 MTX-naïve patients with RA were enrolled in this prospective 76-week cohort study. MTX was initiated, and a predefined dose-escalation protocol was followed. Erythrocyte MTX-PG concentrations were measured using liquid chromatography. The associations of MTX-PG concentrations with disease activity and adverse events were analysed. Results: Dose escalation of MTX resulted in increased MTX-PG concentrations and a decrease in the mean Disease Activity Score in 28 joints (DAS28). A significant association was observed between total MTX-PG concentrations and ΔDAS28 at week 12 (β=-0.013, p=0.003) and at week 24 (β=-0.014, p=0.003). The maximum MTX-PG levels were significantly higher in patients presenting with elevated transaminases (≥100 IU/L) than in those without (146 vs 106 nmol/L, p=0.009). Receiver operating characteristic curve analysis revealed that a total MTX-PG concentrations of 83 nmol/L at week 12 was the threshold for a DAS28 improvement of ≥1.2 at week 24, and 105 nmol/L was the threshold for transaminases of ≥50 IU/L and 131 nmol/L for transaminases of ≥100 IU/L. MTX-PG concentrations were strongly influenced by body mass index and a serum albumin level. Conclusions: MTX-PG concentrations are a useful biomarker in MTX therapy, in terms of efficacy and safety.

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Effect of genetic polymorphisms of azathioprine-metabolizing enzymes on response to rheumatoid arthritis treatment

Tsuchiya A., Aomori T., Sakamoto M., Takeuchi A., Suzuki S., Jibiki A., Otsuka N., Ishioka E., Kaneko Y., Takeuchi T., Nakamura T.

Pharmazie （Pharmazie） 72 （ 1 ） 22 - 28 2017年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0031-7144

© 2017, Govi-Verlag Pharmazeutischer Verlag GmbH. All rights reserved. Azathioprine (AZA) is increasingly being prescribed to rheumatoid arthritis (RA) patients. Following oral administration, AZA is converted into its active form. Inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE) patients with low thiopurine (S)-methyltransferase (TPMT) activity tend to respond well to AZA therapy. In a previous study of Japanese SLE patients under low-dose AZA therapy, the group with the 94C>A mutation in inosine triphosphatase (ITPA) showed greater improvement in their disease activity index. However, it is not yet clear how genotypes relate to responsiveness to RA treatment. The genotypes ITPA 94C>A, TPMT∗3C, NUDT15 595C>T, GST-M1, GST-T1 and MRP4/ABCC4 2269G>A of Japanese patients with RA were determined. The relationship between these genotypes and response to AZA therapy was evaluated using the Disease Activity Score 28 (DAS28) and various medical data. Of the 22 patients 15 had the ITPA 94C/C genotype, 7 had the ITPA 94C/A genotype, none had the TPMT∗3C mutation, 4 had the NUDT15 595C>T mutation, 8 had the GST-M1 and T1 null genotypes and 9 had the MRP4/ABCC4 2269G>A mutation. Changes in DAS28 at 6 months after baseline were similar in both ITPA genotype groups. However, the maintenance dose of AZA was significantly lower in the C/A group than in the C/C group (0.85±0.30 mg/kg/day vs. 1.2±0.46 mg/kg/day, respectively; p = 0.043). The ITPA 94C/A group showed the same response to RA treatment as the C/C group, but at a lower dose. This demonstrates that RA patients with the ITPA 94C>A mutation are more responsive to AZA.

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Treatment of rheumatoid arthritis with biological agents – as a typical and common immune-mediated inflammatory disease

竹内勤

Proceeding of the Japan Academy, series B 93 600 - 608 2017年

単著, 査読有り

Simplified Disease Activity Index remission at month 6 is an independent predictor of functional and structural remissions at month 12 during abatacept treatment in patients with rheumatoid arthritis: A multi-center, prospective cohort study in Japan

Yamazaki H., Hirano F., Takeuchi T., Amano K., Kikuchi J., Kihara M., Yokoyama W., Sugihara T., Nagasaka K., Hagiyama H., Nonomura Y., Sakai R., Tanaka M., Koike R., Nanki T., Kohsaka H., Miyasaka N., Harigai M.

Modern Rheumatology （Modern Rheumatology） 27 （ 5 ） 787 - 794 2017年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2016 Japan College of Rheumatology. Objective: To evaluate association of clinical remission at month 6 with functional and structural remissions at month 12 during abatacept treatment in patients with rheumatoid arthritis (RA). Methods: This 12-month prospective, multicenter cohort study enrolled 168 patients with RA who started abatacept. Outcomes were assessed using composite measures, quality of life indices, and the van der Heijde-modified total Sharp score (mTSS). The logistic regression analysis was applied to identify factors associated with outcomes and their odds ratios (OR) with 95% confidence interval (95% CI). Results: At month 6 and 12, 21.4% and 26.2% of the patients achieved Simplified Disease Activity Index (SDAI) remission (SDAI <3.3), and 40.6% and 41.7% achieved Health Assessment Questionnaire-Disability Index (HAQ-DI <0.5) remission. Among 129 patients whose mTSS progression was evaluated at month 12, 83 (64.3%) achieved structural remission (ΔmTSS ≤0.5 for 12 months). SDAI remission at month 6 was identified as a significant predictor of both functional (OR, 3.732; 95% CI, 1.328–10.489) and structural remissions (OR, 4.301; 95% CI, 1.298–14.243) at month 12 after adjusting for covariates. Conclusions: Aiming for SDAI remission at month 6 is an appropriate strategy to obtain good functional and structural outcomes at month 12.

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Fcγ receptor 3B polymorphism is associated with hypersensitivity reactions to adalimumab in Japanese patients with rheumatoid arthritis

Tsukamoto M., Kameda H., Ohshige T., Kaneko Y., Yoshimoto K., Suzuki K., Takeuchi T.

Modern Rheumatology （Modern Rheumatology） 27 （ 5 ） 778 - 781 2017年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2016 Japan College of Rheumatology. Objectives: To examine the association between Fcγ receptor (FcγR) polymorphisms and the development of hypersensitivity reactions to adalimumab in patients with rheumatoid arthritis. Methods: Sixty-five patients receiving adalimumab were enrolled in the study. Genetic polymorphisms for FcγR3B were genotyped in FCGR3B NA1/2 alleles by real allelic discrimination assay. Clinical information and the occurrence of a hypersensitivity reaction to adalimumab were collected from the patients’ charts. Results: A hypersensitivity reaction was observed in 12% of the patients. Clinical information obtained from patients with a reaction and those without were the same. The FCGR3B NA1/NA1, NA1/NA2, and NA2/NA2 alleles were found in 75%, 13%, and 13% of the patients with hypersensitivity reaction, respectively, and in 28%, 42%, and 30% of those without a hypersensitivity reaction, respectively (p = 0.04). Multivariate logistic regression analysis identified only the NA1/NA1 as an independent relevant factor for a hypersensitivity reaction to adalimumab (OR 7.7, p = 0.01). Conclusions: The FCGR3B NA1/NA1 genotype is associated with hypersensitivity reactions to adalimumab.

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Treatment of rheumatoid arthritis with biological agents-as a typical and common immune-mediated inflammatory disease

Takeuchi T.

Proceedings of the Japan Academy Series B: Physical and Biological Sciences （Proceedings of the Japan Academy Series B: Physical and Biological Sciences） 93 （ 8 ） 600 - 608 2017年

研究論文（学術雑誌）, 査読有り, ISSN 03862208

© 2017 The Japan Academy. 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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Safety of biologic agents in elderly patients with rheumatoid arthritis

Murota A., Kaneko Y., Yamaoka K., Takeuchi T.

Journal of Rheumatology （Journal of Rheumatology） 43 （ 11 ） 1984 - 1988 2016年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

Objective. To clarify the safety of biologics in elderly patients with rheumatoid arthritis. Methods. Biologics were analyzed for safety in relation to age in 309 patients. Results. Young (< 65 yrs old, n = 174), elderly (65-74 yrs old, n = 86), and older elderly patients (? 75 yrs old, n = 49) were enrolled. Although the incidence of adverse events causing treatment withdrawal was significantly higher in elderly and old elderly compared with young patients, no difference was found between elderly and older elderly patients. Pulmonary complications were independent risk factors. Conclusion. Old patients require special attention, although the safety of biologics in those ? 75 years old and 65-74 was comparable.

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Baricitinib, méthotrexate, ou baricitinib associé au méthotrexate chez les patients ayant une polyarthrite rhumatoïde (PR) récente qui ont reçu peu ou pas de traitements de fond (DMARDs) : Résultats de l'essai de phase 3 RA-BEGIN

Fleischmann R., Takeuchi T., Schlichting D., Macias W., Rooney T., Gurbuz S., Stoykov I., Beattie S., Kuo W., Schiff M., Dougados M.

Revue du Rhumatisme (Edition Francaise) （Revue du Rhumatisme (Edition Francaise)） 83 2016年11月

研究論文（学術雑誌）, 査読有り, ISSN 11698330

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Elevated serum krebs von den lungen-6 in early disease predicts subsequent deterioration of pulmonary function in patients with systemic sclerosis and interstitial lung disease

Kuwana M., Shirai Y., Takeuchi T.

Journal of Rheumatology （Journal of Rheumatology） 43 （ 10 ） 1825 - 1831 2016年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

© Copyright 2016. All rights reserved. Objective. To identify predictors of poor prognosis in patients with systemic sclerosis (SSc) associated with interstitial lung disease (ILD). Methods. Fifty patients with early-stage SSc-ILD who had never received disease-modifying drugs and were either observed for ≥ 10 years or died from ILD-related causes were enrolled. The baseline variables of patients who developed endstage lung disease (ESLD) were compared with those of patients who remained ESLD-free, and the Cox proportional hazard model was used to identify initial factors that correlated with ESLD development. Results. Sixteen patients (32%) developed ESLD during 173.5 64.7 months of followup. Elevated serum Krebs von den Lungen-6 (KL-6) at initial assessment was highly correlated with ESLD development (p = 0.0002). Receiver-operating characteristic curve analysis revealed that a KL-6 value of 1273 U/ml effectively discriminated patients who developed ESLD from those who did not. Patients with KL-6 > 1273 U/ml were less likely to remain ESLD-free compared with those with lower KL-6 levels (p < 0.0001). Multivariate analysis showed that KL-6 > 1273 U/ml was the most reliable predictor of ESLD development (OR 51.2, 95% CI 7.6-343, p < 0.0001). Finally, the initial KL-6 level correlated with the forced vital capacity (FVC) decline rate (r = 0.58, p < 0.0001). Conclusion. The natural course of SSc-ILD is highly variable. Baseline serum KL-6 is a biomarker potentially useful for predicting FVC decline.

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Bendamustine increases interleukin-10 secretion from B cells via p38 MAP kinase activation

Lu L., Yoshimoto K., Morita A., Kameda H., Takeuchi T.

International Immunopharmacology （International Immunopharmacology） 39 273 - 279 2016年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1567-5769

© 2016 Elsevier B.V. We investigated the effects of bendamustine on B cell functions and explored potential clinical applications of the drugs to autoimmune diseases. Proliferation of Ramos cells, a human B cell line, was significantly inhibited by 25–100 μM of bendamustine in a dose-dependent manner. Concordantly, IgM secretion from Ramos cells was significantly inhibited at these concentrations by up to 70%. Interestingly, however, the production and secretion of interleukin-10 (IL-10) were dramatically (at least > 10-fold) increased by bendamustine at growth inhibitory concentrations. Exploration of the molecular mechanism of IL-10 production revealed that bendamustine enhanced the phosphorylation of p38 MAP kinase. Further, Sp1 was identified as a downstream transcription factor, and the inhibition of p38 MAP kinase and Sp1 with their inhibitors led to the abrogation of bendamustine-induced IL-10 production and the DNA binding of Sp1. Importantly, when PBMC from healthy donors were cultured with bendamustine at the concentration of 30 μM, under the stimulation with an anti-IgM antibody, an anti-CD40 antibody, recombinant human IL-21 (rhIL-21) and recombinant human soluble BAFF (rhsBAFF), IL-10 production by B cells (CD20+CD4-CD8-CD14-) among peripheral blood mononuclear cell (PBMC) was significantly enhanced by adding bendamustine. These results collectively suggest that the p38 MAP kinase-Sp1 pathway plays a crucial role in bendamustine-induced IL-10 production by B cells. Our findings suggest a novel therapeutic possibility for autoimmune diseases through the upregulation of IL-10 which has an anti-inflammatory effects.

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Safety and efficacy of CT-P13 in Japanese patients with rheumatoid arthritis in an extension phase or after switching from infliximab

竹内勤

Modern Rheumatology （Modern Rheumatology） 27 （ 2 ） 237 - 245 2016年09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. Objectives: This study aimed to evaluate the safety of CT-P13 in patients with rheumatoid arthritis (RA) during long-term treatment or after switching from innovator infliximab (IFX). Methods: Patients who completed 54 weeks of treatment in a phase I/II study (PI/II) received CT-P13 at an initial dose of 3 mg/kg at Week 62, with dose increases permitted up to 10 mg/kg. The primary endpoint was adverse event (AE) incidence. Results: Thirty-four of 38 patients in the maintenance group and 29 of 33 in the switch group reported at least one AE. Safety profiles in both groups were similar to those in PI/II. Eleven of 28 patients who were positive for anti-drug antibodies (ADA) at Week 62 discontinued the study before Week 110. Forty-one of 43 ADA-negative patients remained negative, and 10 of 28 ADA-positive patients became negative during the study. The mean DAS28 (ESR) at Week 134 was 3.166 in the maintenance group and 3.955 in the switch group. Conclusions: CT-P13 was well tolerated in patients who maintained the treatment after 54 weeks and in patients who switched to CT-P13 after 54 weeks of IFX treatment. The study also demonstrated a stable clinical efficacy of CT-P13 in RA patients.

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Toreforant, a histamine H4 receptor antagonist, in patients with active rheumatoid arthritis despite methotrexate therapy: Results of 2 phase II studies

Thurmond R., Greenspan A., Radziszewski W., Xu X., Miao Y., Chen B., Ge T., Zhou B., Baker D., Pavlova D., Ritchlin C., Tanaka Y., Takeuchi T., Smolen J.

Journal of Rheumatology （Journal of Rheumatology） 43 （ 9 ） 1637 - 1642 2016年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

Copyright © 2016. All rights reserved. Objective. To assess toreforant (selective histamine H 4 receptor antagonist) in active rheumatoid arthritis (RA). Methods. In a phase IIa, double-blind, placebo-controlled test, 86 patients were randomized (2:1) to once-daily toreforant 100 mg or placebo for 12 weeks. In phase IIb, double-blind, placebo-controlled, dose-range-finding evaluations, 272 patients were randomized (1:1:1:1) to once-daily placebo or toreforant 3/10/30 mg. Primary efficacy endpoints for both studies were Week 12 changes in 28-joint Disease Activity Score-C-reactive protein (DAS28-CRP). Results. Phase IIa testing was terminated prematurely (patient fatality; secondary hemophagocytic lymphohistiocytosis). Posthoc analyses indicated toreforant 100 mg/day reduced RA signs/symptoms through Week 12. Phase IIb testing, however, showed no significant Week 12 improvement in DAS28-CRP with toreforant. Conclusion. Toreforant was not effective in phase IIb testing.

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Discontinuation of etanercept after achievement of sustained remission in patients with rheumatoid arthritis who initially had moderate disease activity—results from the ENCOURAGE study, a prospective, international, multicenter randomized study

Yamanaka H., Nagaoka S., Lee S., Bae S., Kasama T., Kobayashi H., Nishioka Y., Ueki Y., Seto Y., Nishinarita M., Tamura N., Kimura N., Saito K., Tomita T., Nawata Y., Suzuki S., Ishigatsubo Y., Munakata Y., Makino Y., Inoue E., Tanaka Y., Takeuchi T.

Modern Rheumatology （Modern Rheumatology） 26 （ 5 ） 651 - 661 2016年09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 investigate the efficacy and safety of etanercept (ETN) in patients with rheumatoid arthritis (RA) with moderate disease activity and the possibility to discontinue ETN after achieving remission. Methods: Multicenter, randomized, and open-label study was conducted in Japan and Korea. RA patients (disease duration <5 years) with moderate disease activity despite methotrexate (MTX) treatment were allocated to either MTX or ETN + MTX (Period 1) for 12 months. Patients who achieved sustained remission defined as DAS28 < 2.6 at both 6 and 12 months in the ETN + MTX group, were randomized to either continue or discontinue ETN for 12 months (Period 2). Results: A total of 222 patients were enrolled in Period 1 and clinical remission was achieved in 106/157 (67.5%) and 5/28 (17.9%) patients in the ETN + MTX and MTX groups, respectively. In Period 2, sixty-seven patients were randomized and finally 28/32 (87.5%) and 15/28 (53.6%) patients who continued or discontinued ETN maintained clinical remission. Baseline disease activity and the presence of comorbid diseases influenced the maintenance of remission after ETN discontinuation. Conclusions: ETN + MTX was efficient for RA patients with moderate disease activity into remission. After achieving sustained remission, a half of the patients who discontinued ETN could maintain remission for 1 year.

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Polychondritis presenting with oculomotor and abducens nerve palsies as the initial manifestation

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

Modern Rheumatology （Modern Rheumatology） 26 （ 5 ） 790 - 793 2016年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2014 Japan College of Rheumatology. We treated a patient with relapsing polychondritis (RP) who presented with intermittent oculomotor and abducens nerve palsies as the first manifestation. Ear swelling and laryngeal edema emerged 7 months later, which led us to diagnose him with RP. Moderate doses of glucocorticoid resolved all symptoms. Our experience with RP accompanied by oculomotor nerve palsy suggests that RP should be considered in patients with cranial nerve palsies so that they may be promptly diagnosed and treated.

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Efficacy and safety of tabalumab plus standard of care in Japanese patients with active systemic lupus erythematosus: Subgroup analyses of the ILLUMINATE-1 study

Tanaka Y., Takeuchi T., Akashi N., Takita Y., Kovacs B., Kariyasu S.

Modern Rheumatology （Modern Rheumatology） 27 （ 2 ） 284 - 291 2016年07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 assess the efficacy and safety of tabalumab, an anti-B cell activating factor (BAFF) antibody, in combination with standard of care (SoC) therapy in Japanese patients with active systemic lupus erythematosus (SLE). Methods: A subgroup analysis was conducted in Japanese patients (n = 45) enrolled in ILLUMINATE-1, a phase III global trial in SLE patients (N = 1164). Patients received SoC plus tabalumab or placebo, starting with a loading dose (240 mg) at week 0, followed by 120 mg every 4 weeks (120 Q4W, n = 15), 120 mg every 2 weeks (120 Q2W, n = 15), or placebo Q2W (n = 15). The primary endpoint was proportion achieving SLE Responder Index-5 (SRI-5) improvement at week 52. Results: A numerically greater SRI-5 response rate was achieved with 120 Q2W (46.7%; p = 0.059 vs. placebo) compared with 120 Q4W (20.0%) and placebo Q2W (13.3%). The proportion of patients with severe SLE flare was lower for 120 Q2W (0%) and 120 Q4W (6.7%) than for placebo (26.7%). The rates of serious adverse events (AEs) and treatment-emergent AEs were similar across treatments. Conclusion: In Japanese SLE patients, tabalumab 120 Q2W improved SRI-5 response rate and reduced the frequency of severe flares compared with placebo. Safety profiles were similar with tabalumab and placebo.

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Identification of baseline gene expression signatures predicting therapeutic responses to three biologic agents in rheumatoid arthritis: A retrospective observational study

Nakamura S., Suzuki K., Iijima H., Hata Y., Lim C., Ishizawa Y., Kameda H., Amano K., Matsubara K., Matoba R., Takeuchi T.

Arthritis Research and Therapy （Arthritis Research and Therapy） 18 （ 1 ） 159 2016年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1478-6354

© 2016 The Author(s). Background: According to EULAR recommendations, biologic DMARDs (bDMARDs) such as tumor necrosis factor inhibitor, tocilizumab (TCZ), and abatacept (ABT) are in parallel when prescribing to rheumatoid arthritis (RA) patients who have shown insufficient response to conventional synthetic DMARDs. However, most prediction studies of therapeutic response to bDMARDs using gene expression profiles were focused on a single bDMARD, and consideration of the results from the perspective of RA pathophysiology was insufficient. The aim of this study was to identify the specific molecular biological features predicting the therapeutic outcomes of three bDMARDs (infliximab [IFX], TCZ, and ABT) by studying blood gene expression signatures of patients before biologic treatment in a unified test platform. Methods: RA patients who responded inadequately to methotrexate and were later commenced on any one of IFX (n = 140), TCZ (n = 38), or ABT (n = 31) as their first biologic between May 2007 and November 2011 were enrolled. Whole-blood gene expression data were obtained before biologic administration. Patients were categorized into remission (REM) and nonremission (NON-REM) groups according to CDAI at 6 months of biologic therapy. We employed Gene Set Enrichment Analysis (GSEA) to identify functional gene sets differentially expressed between these two groups for each biologic. Then, we compiled "signature scores" for these gene sets, and the prediction performances were assessed. Results: GSEA showed that inflammasome genes were significantly upregulated with IFX in the NON-REM group compared with the REM group. With TCZ in the REM group, B-cell-specifically expressed genes were upregulated. RNA elongation, apoptosis-related, and NK-cell-specifically expressed genes were upregulated with ABT in the NON-REM group. Logistic regression analyses showed that "signature scores" of inflammasomes, B-cell-specifically expressed, and NK-cell-specifically expressed genes were significant, independently predictive factors for treatment outcome with IFX, TCZ, and ABT, respectively. The AUCs of ROC curves of these signature scores were 0.637, 0.796, and 0.768 for IFX, TCZ, and ABT, respectively. Conclusions: We have identified original gene expression predictive signatures uniquely underlying the therapeutic effects of IFX, TCZ, and ABT. This is, to our knowledge, the first attempt to predict therapeutic effects of three drugs concomitantly using a unified gene expression test platform.

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Enhanced IgG4 production by follicular helper 2 T cells and the involvement of follicular helper 1 T cells in the pathogenesis of IgG4-related disease

Akiyama M., Yasuoka H., Yamaoka K., Suzuki K., Kaneko Y., Kondo H., Kassai Y., Koga K., Miyazaki T., Morita R., Yoshimura A., Takeuchi T.

Arthritis Research and Therapy （Arthritis Research and Therapy） 18 （ 1 ） 167 2016年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1478-6354

© 2016 The Author(s). Background: The aim of this study was to elucidate the function of circulating follicular helper T (Tfh) cell subsets in helping B cells in patients with active, untreated IgG4-related disease (IgG4-RD) and determine their relationship with disease activity. Methods: Seventeen consecutive patients with active, untreated IgG4-RD, 20 with primary Sjögren syndrome (pSS), 5 with multicentric Castleman's disease (MCD), and 12 healthy controls (HC) were enrolled. Tfh cell subset function was evaluated by co-culture with naïve B cells in vitro. Activated Tfh cell subsets were defined as a CCR7lowPD-1high subset among Tfh cell subsets. Disease activity was evaluated by IgG4-RD responder index (IgG4-RD RI) score. Results: The number of Tfh2 cells was significantly higher in IgG4-RD compared to pSS, MCD, or HC, and correlated with serum IgG4 level or the number of plasmablasts. In vitro, Tfh2 cells more efficiently induced the differentiation of naïve B cells into plasmablasts compared to Tfh1 or Tfh17 cells. Of note, while IgG production in culture supernatants of Tfh2 cells was comparable between IgG4-RD and HC, IgG4 production was significantly higher with Tfh2 cells from patients with IgG4-RD than in those from HC. Accordingly, the IgG4:IgG ratio in culture supernatants was also significantly higher with Tfh2 cells from IgG4-RD compared to HC. Moreover, the number of activated Tfh2 cells was higher in IgG4-RD compared to pSS, MCD, or HC, and strongly correlated with IgG4-RD RI score in the baseline active phase. Particularly, the number of activated Tfh2 cells was associated with the number of affected organs and serum IgG4 level. Importantly, the number of activated Tfh2 cells was decreased after glucocorticoid treatment and paralleled disease improvement. Moreover, the number of activated Tfh1 cells was also increased in IgG4-RD compared to pSS, MCD, or HC, correlating with IgG4-RD RI score, but not with serum IgG4 level. Conclusions: Tfh2 cells, but not Tfh1 or Tfh17 cells, induce the differentiation of naïve B cells into plasmablasts and enhanced production of IgG4 in patients with active, untreated IgG4-RD. Furthermore, activated Tfh2 cells reflect disease activity, suggesting the involvement of this T cell subset in the pathogenesis of IgG4-RD. Interestingly, the number of activated Tfh1 cells was also increased in IgG4-RD, correlating with disease activity but not with serum IgG4 level, suggesting the involvement of Tfh1 cells but not in the process of IgG4 production in patients with IgG4-RD.

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Efficacy of denosumab combined with bDMARDs on radiographic progression in rheumatoid arthritis

Hasegawa Tetsuo, Kaneko Yuko, Izumi Keisuke, Takeuchi Tsutomu

Joint Bone Spine 84 （ 3 ） 379 - 380 2016年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1297-319X

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Effect of denosumab on Japanese patients with rheumatoid arthritis: A dose-response study of AMG 162 (Denosumab) in patients with rheumatoid arthritis on methotrexate to validate inhibitory effect on bone erosion (DRIVE) - A 12-month, multicentre, randomised, double-blind, placebo-controlled, phase II clinical trial

Takeuchi T., Tanaka Y., Ishiguro N., Yamanaka H., Yoneda T., Ohira T., Okubo N., Genant H., Van Der Heijde D.

Annals of the Rheumatic Diseases （Annals of the Rheumatic Diseases） 75 （ 6 ） 983 - 990 2016年07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 three different regimens of denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor kappa B (RANK) ligand (RANKL), for Japanese patients with rheumatoid arthritis (RA). Methods In this multicentre, randomised, placebocontrolled phase II study, 350 Japanese patients with RA between 6 months and <5 years, stratified by glucocorticoid use and rheumatoid factor status, were randomly assigned to subcutaneous injections of placebo or denosumab 60 mg every 6 months (Q6M), every 3 months (Q3M) or every 2 months (Q2M). All patients basically continued methotrexate treatment and had a supplement of calcium and vitamin D throughout the study. The primary endpoint was change in the modified Sharp erosion score from baseline to 12 months. Results Denosumab significantly inhibited the progression of bone erosion at 12 months compared with the placebo, and the mean changes of the modified Sharp erosion score at 12 months from baseline were 0.99, 0.27 (compared with placebo, p=0.0082), 0.14 (p=0.0036) and 0.09 (p<0.0001) in the placebo, Q6M, Q3M and Q2M, respectively. Secondary endpoint analysis revealed that denosumab also significantly inhibited the increase of the modified total Sharp score compared with the placebo, with no obvious evidence of an effect on joint space narrowing for denosumab. As shown in previous studies, denosumab increased bone mineral density. No apparent difference was observed in the safety profiles of denosumab and placebo. Conclusions Addition of denosumab to methotrexate has potential as a new therapeutic option for patients with RA with risk factors of joint destruction.

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Post-hoc analysis showing better clinical response with the loading dose of certolizumab pegol in Japanese patients with active rheumatoid arthritis

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

Modern Rheumatology （Modern Rheumatology） 26 （ 4 ） 473 - 480 2016年07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 compare the efficacy and safety of certolizumab pegol (CZP) with and without loading dose (LD) in a post-hoc analysis of two Japanese clinical studies. Methods: Data from the double-blind trials (DBT) J-RAPID and HIKARI, and their open-label extension (OLE) studies, were used. Patients randomized to CZP 200 mg every 2 weeks (Q2W) groups starting with LD (400 mg Weeks 0/2/4; LD group; J-RAPID: n = 82, HIKARI: n = 116) and patients randomized to placebo groups who subsequently started CZP Q2W without LD in the OLEs (No-LD group; J-RAPID: n = 61, HIKARI: n = 99) were analyzed. Efficacy and pharmacokinetics were assessed during 24 weeks. Adverse events were reported from all studies. Results: In both trials, the LD groups showed more rapid initial ACR20/50/70 kinetics, and maintained higher ACR50/70 responses until 24 weeks, compared with the No-LD groups. Anti-CZP antibody development was less frequent in the LD groups (J-RAPID: 1.2% versus 4.9%; HIKARI: 17.2% versus 27.3%). Similar safety profiles were reported between LD and No-LD groups (any AEs: 281.8 versus 315.7 [J-RAPID], 282.6 versus 321.3 [HIKARI] [incidence rate/100 patient-years]). Conclusions: Despite limitations, including comparing DBT and OLE studies, these results suggest that a CZP LD improves clinical response in active rheumatoid arthritis without altering the safety profile.

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Clinical efficacy, radiographic progression, and safety through 156 weeks of therapy with subcutaneous golimumab in combination with methotrexate in Japanese patients with active rheumatoid arthritis despite prior methotrexate therapy: final results of the randomized GO-FORTH trial

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

Modern Rheumatology （Modern Rheumatology） 26 （ 4 ） 481 - 490 2016年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2015 Japan College of Rheumatology. Objective: To evaluate the safety and efficacy of golimumab + methotrexate (MTX) in Japanese patients with active rheumatoid arthritis (RA). Methods: Japanese patients with active RA despite MTX were randomized to placebo + MTX (Group 1, n = 88), golimumab 50 mg + MTX (Group 2, n = 86), or golimumab 100 mg + MTX (Group 3, n = 87). Patients with <20% improvement in swollen/tender joint counts entered early escape at week 16. At week 24, all remaining placebo patients crossed over to golimumab 50 mg. Efficacy assessments included ACR20, DAS28-ESR, and HAQ-DI. Radiographic progression was assessed with the van der Heijde-modified Sharp (vdH-S) score. Results: ACR20 response rates in Group 1, Group 2, and Group 3 were 67.9, 86.1, and 82.4%, respectively, at week 52 and were maintained through week 104 (87.1, 94.0, and 88.7%) and week 156 (97.1, 94.1, and 89.5%). Proportions of patients with good/moderate DAS28-ESR response or clinically meaningful improvement in HAQ-DI were also maintained through week 156. The majority of patients did not experience radiographic progression through week 156. Among 257 golimumab-treated patients, 251 (97.7%) had ≥1 AE; 54 (21.0%) had ≥1 serious AE through week 156. Infections were the most common type of AE. Conclusions: Response to golimumab + MTX was maintained over 3 years in Japanese patients with active RA despite MTX. Safety results were consistent with the known safety profile of golimumab.

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Akiyama M., Kaneko Y., Hayashi Y., Takeuchi T.

Medicine (United States) （Medicine (United States)） 95 （ 24 ） e3970 2016年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0025-7974

© 2016 Wolters Kluwer Health, Inc. All rights reserved. Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized new disease entity characterized by elevated serum IgG4 and infiltration of IgG4+ plasma cells in affected tissues. Histological examination is essential for definitive diagnosis, as other pathological conditions can also present with serum IgG4 elevation. However, IgG4-RD frequently involves vital or internal organs that are difficult to perform biopsies. We herein report a unique case of IgG4-RD involving vital organs that could be successfully diagnosed by alternative lip biopsy, an accessible, little invasive procedure, despite no apparent manifestation demonstrating the involvement in labial salivary gland. A 60-year-old man with swelling of both submandibular glands and elevated serum creatinine level visited our hospital. His labial salivary glands appeared normal. His blood test showed high serum IgG4, and positron-emission computed tomography revealed abnormal uptake in submandibular glands, periaorta, and left kidney with hydronephrosis. We suspected him of IgG4-RD; however, the involved organs were difficult to approach for histological examination. Alternatively, we performed lip biopsy and proved massive infiltration of IgG4+ plasma cells leading to the diagnosis with IgG4-RD. Treatment with prednisolone resulted in the remarkable improvement of organ involvements and the normalization of serum IgG4 level after 3 months. Prednisolone was gradually tapered without the relapse of disease. The early recognition and diagnosis of IgG4-RD is clinically important because delay in the treatment initiation leads to fibrosis with irreversible organ damage. Our case highlights the possibility that lip biopsy is a promising option for histological examination in patients with IgG4-RD in whom affected organs are difficult to access, leading to early diagnosis with appropriate treatment.

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Methotrexate-associated intravascular large B-cell lymphoma in a patient with rheumatoid arthritis

Kikuchi J., Kaneko Y., Kasahara H., Emoto K., Kubo A., Okamoto S., Takeuchi T.

Internal Medicine （Internal Medicine） 55 （ 12 ） 1661 - 1665 2016年06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. Intravascular large B-cell lymphoma (IVLBCL) is a rare and clinically aggressive lymphoma with an unfavorable prognosis. We report the case of a 50-year-old woman who was diagnosed with IVLBCL during treatment with methotrexate (MTX) and biologic agents for rheumatoid arthritis. The symptoms showed partial improvement only after the cessation of both treatments. She subsequently received chemotherapy and achieved a complete remission and has remained free of recurrence for 2 years without any further treatment. We herein describe a rare case of IVLBCL which presented with the features of an MTX-associated lymphoproliferative disorder.

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Efficacy and safety of the oral Janus kinase inhibitor peficitinib (ASP015K) monotherapy in patients with moderate to severe rheumatoid arthritis in Japan: A 12-week, randomised, double-blind, placebo-controlled phase IIb study

Takeuchi T., Tanaka Y., Iwasaki M., Ishikura H., Saeki S., Kaneko Y.

Annals of the Rheumatic Diseases （Annals of the Rheumatic Diseases） 75 （ 6 ） 1057 - 1064 2016年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

Objective To evaluate the efficacy, safety and dose response of a novel oral Janus kinase inhibitor, peficitinib (ASP015K), as monotherapy in Japanese patients with moderate to severe rheumatoid arthritis (RA). Methods In a 12-week, double-blind study, 281 adult patients with RA with active disease not on concomitant disease-modifying antirheumatic drug therapy were randomised equally to once-daily placebo or peficitinib 25, 50, 100 and 150 mg. The primary endpoint was American College of Rheumatology (ACR) 20 response in the peficitinib treatment groups versus placebo at week 12. Results Mean age was 53.0 years, 81.1% were female and 25.3% had previously used antitumour necrosis factor therapy. Peficitinib 50, 100 and 150 mg each showed statistically significantly higher ACR20 response rates compared with placebo, and response rates increased up to 150 mg with a statistically significant dose response. The total incidence of treatmentemergent adverse events (TEAEs) was similar between the placebo (64.3%) and peficitinib 25, 50, 100 and 150 mg groups (70.9%, 64.9%, 52.7% and 67.2%, respectively). TEAEs occurring more frequently in the peficitinib group compared with the placebo group included nasopharyngitis, increased blood creatine phosphokinase and diarrhoea. No cases of serious infections were reported. Herpes zoster occurred in four patients (two each in peficitinib 25 and 100 mg). Conclusions Treatment with peficitinib as monotherapy for 12 weeks in Japanese patients with moderate to severe RA is efficacious and showed acceptable safety profile. These findings support further developments of peficitinib for RA treatment.

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IL-6 blockade

Kaneko Y., Takeuchi T.

Nihon rinsho. Japanese journal of clinical medicine （Nihon rinsho. Japanese journal of clinical medicine） 74 （ 6 ） 963 - 967 2016年06月

研究論文（学術雑誌）, 査読有り, ISSN 00471852

Interleukin-6 (IL-6) plays an important role in the pathogenesis of rheumatoid arthritis (RA). Tocilizumab, anti-human IL-6 receptor monoclonal antibody developed in Japan, prevents IL-6 from binding to IL-6 receptor blocking IL-6 signal. The clinical and radiographic efficacy of tocilizumab has proved in many clinical studies. Tocilizumab monotherapy is superior to methotrexate, which has not proved in TNF inhibitors, although tocilizuab in combination with methotrexate is more effective than tocilizumab monotherapy in inducing remission. Hepatotoxicity and infection are adverse events to be careful about.

Alteration of matrix metalloproteinase-3 O-glycan structure as a biomarker for disease activity of rheumatoid arthritis

Takeshita M., Kuno A., Suzuki K., Matsuda A., Shimazaki H., Nakagawa T., Otomo Y., Kabe Y., Suematsu M., Narimatsu H., Takeuchi T.

Arthritis Research and Therapy （Arthritis Research and Therapy） 18 （ 1 ） 112 2016年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1478-6354

© 2016 Takeshita et al. Background: Nearly all secreted proteins are glycosylated, and serum glycoproteins that exhibit disease-associated glycosylation changes have potential to be biomarkers. In rheumatoid arthritis (RA), C-reactive protein (CRP), and matrix metalloproteinase-3 (MMP-3) are widely used as serologic biomarkers, but they lack sufficient specificity or precision. We performed comparative glycosylation profiling of MMP-3 using a recently developed antibody-overlay lectin microarray technology that allows semicomprehensive and quantitative analysis of specific protein glycosylation to develop an RA-specific disease activity biomarker. Methods: Serum was taken from patients with RA (n = 24) whose disease activity was scored using composite measures, and MMP-3 was immunoprecipitated and subjected to lectin microarray analysis. A disease activity index (DAI) based on lectin signal was developed and validated using another cohort (n = 60). Synovial fluid MMP-3 in patients with RA and patients with osteoarthritis (OA) was also analyzed. Results: Intense signals were observed on a sialic acid-binding lectin (Agrocybe cylindracea galectin [ACG]) and O-glycan-binding lectins (Jacalin, Agaricus bisporus agglutinin [ABA], and Amaranthus caudatus agglutinin [ACA]) by applying subnanogram levels of serum MMP-3. ACG, ABA, and ACA revealed differences in MMP-3 quantity, and Jacalin revealed differences in MMP-3 quality. The resultant index, ACG/Jacalin, correlated well with disease activity. Further validation using another cohort confirmed that this index correlated well with several DAIs and their components, and reflected DAI changes following RA treatment, with correlations greater than those for MMP-3 and CRP. Furthermore, MMP-3, which generated a high ACG/Jacalin score, accumulated in synovial fluid of patients with RA but not in that of patients with OA. Sialidase digestion revealed that the difference in quality was derived from O-glycan α-2,6-sialylation. Conclusions: This is the first report of a glycoprotein biomarker using glycan change at a local lesion to assess disease activity in autoimmune diseases. Differences in the degree of serum MMP-3 α-2,6-sialylation may be a useful index for estimating disease activity.

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Identification of definitive serum biomarkers associated with disease activity in primary Sjögren's syndrome

Nishikawa A., Suzuki K., Kassai Y., Gotou Y., Takiguchi M., Miyazaki T., Yoshimoto K., Yasuoka H., Yamaoka K., Morita R., Yoshimura A., Takeuchi T.

Arthritis Research and Therapy （Arthritis Research and Therapy） 18 （ 1 ） 106 2016年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1478-6354

© 2016 Nishikawa et al. Background: In this study, we sought to identify definitive biomarkers associated with disease activity in primary Sjögren's syndrome (pSS). Methods: Serum protein concentrations in pSS patients and healthy controls (HCs) were comprehensively screened using high-throughput proteomic analysis, and differentially expressed proteins were extracted. Correlation between differentially expressed proteins and European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI) scores was analyzed and disease activity-associated biomarkers were identified. These biomarkers were validated by enzyme-linked immunosorbent assay (ELISA) in a separate pSS cohort. Results: The serum concentrations of 1100 proteins were compared between 30 pSS patients and 30 HCs, with 82 differentially expressed proteins identified as pSS-associated proteins. Of these 82 proteins, 9 were identified as disease activity-associated biomarkers. These nine biomarkers underwent validation by ELISA in a separate pSS validation cohort (n = 58), with five proteins (CXCL13, TNF-R2, CD48, B-cell activating factor (BAFF), and PD-L2) subsequently being confirmed as candidate biomarkers. Of these five candidate biomarkers, CXCL13 exhibited the most significant correlation with the lymphadenopathy, glandular, and pulmonary domains of the ESSDAI. CXCL13, TNF-R2 and CD48 exhibited a positive correlation with the biological domain of the ESSDAI. TNF-R2 exhibited the most negative correlation with uptake in the submandibular gland on technetium 99m-pertechnetate salivary gland scintigraphy. Conclusions: Our approach successfully identified serum biomarkers associated with disease activity in pSS patients. These markers might be potential therapeutic targets in pSS patients.

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Enlargement of thymoma triggers overlapping autoimmune diseases

Shiihashi Gen, Kaneko Yuko, Suzuki Shigeaki, Hanaoka Hironari, Nakahara Jin, Takeuchi Tsutomu, Suzuki Norihiro

Autoimmunity Reviews 15 （ 12 ） 1200 - 1201 2016年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1568-9972

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Association of disease activity with acute exacerbation of interstitial lung disease during tocilizumab treatment in patients with rheumatoid arthritis: a retrospective, case–control study

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

Rheumatology International （Rheumatology International） 36 （ 6 ） 881 - 889 2016年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0172-8172

© 2016, Springer-Verlag Berlin Heidelberg. The objective of the study was to identify risk factors for acute exacerbation of interstitial lung disease (ILD) during tocilizumab treatment in patients with rheumatoid arthritis (RA). This is a retrospective, case–control study. We reviewed 395 consecutive RA patients who received tocilizumab. First, we divided the patients according to the presence (RA-ILD) or absence of ILD (non-ILD) assessed by chest X-ray or high-resolution computed tomography, and compared them for characteristics relevant to RA-ILD. Subsequently, focusing on the patients with RA-ILD, we assessed their baseline characteristics and clinical courses comparing patients with acute exacerbation to those without. Comparing 78 with ILD and 317 without ILD, the following were identified as factors related to RA-ILD on multivariate analysis: age 60 years or older (OR 4.5, 95 % CI 2.2–9.4, P < 0.0001), smoking habit (OR 2.9, 95 % CI 1.5–5.5, P = 0.002), and high rheumatoid factor levels (OR 2.8, 95 % CI 1.4–5.5, P = 0.002). Of 78 RA-ILD patients, six developed acute exacerbation during tocilizumab treatment. The median duration between the initiation of tocilizumab treatment and the acute exacerbation occurrence was 48 weeks. While baseline characteristics did not differ between acute exacerbation and non-acute exacerbation groups, patients experiencing acute exacerbation had significantly higher Clinical Disease Activity Index (CDAI) at 24 weeks (20.8 vs. 6.2, P = 0.019). Univariate analysis showed that CDAI > 10 at 24 weeks was a risk factor for acute exacerbation (OR 4.7, 95 % CI 2.1–10.4, P = 0.02). Uncontrolled arthritis activity during tocilizumab treatment may be associated with acute exacerbation of RA-ILD, suggesting post-treatment monitoring of disease activity is important not only with respect to RA itself but also for RA-ILD.

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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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The efficacy and safety of subcutaneous clazakizumab in patients with moderate-to-severe rheumatoid arthritis and an inadequate response to methotrexate: results from a multinational, phase IIb, randomized, double-blind, placebo/active-controlled, dose-ranging study

Weinblatt M., Mease P., Mysler E., Takeuchi T., Drescher E., Berman A., Xing J., Zilberstein M., Banerjee S., Emery P.

Arthritis & rheumatology (Hoboken, N.J.) （Arthritis & rheumatology (Hoboken, N.J.)） 67 （ 10 ） 2591 - 2600 2015年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2326-5191

© 2015, American College of Rheumatology. OBJECTIVE: Clazakizumab is a humanized monoclonal antibody that binds to the interleukin-6 (IL-6) cytokine. This study was undertaken to evaluate the efficacy and safety of clazakizumab in combination with methotrexate (MTX) or clazakizumab monotherapy versus MTX alone in patients with rheumatoid arthritis (RA) and an inadequate response to MTX.METHODS: In this multinational, phase IIb, randomized, double-blind, placebo-controlled, dose-ranging study, patients were randomized to receive 1) once-monthly subcutaneous (SC) clazakizumab at 25, 100, or 200 mg plus MTX, 2) once-monthly SC clazakizumab at 100 mg or 200 mg as monotherapy, or 3) MTX plus placebo (i.e., MTX alone). Adalimumab (40 mg) plus MTX was included as an active reference. The primary end point was the American College of Rheumatology 20% (ACR20) improvement response rate at week 12. Secondary end points included ACR20, ACR50, and ACR70 response rates as well as protocol-defined remission rates and Health Assessment Questionnaire disability index scores at weeks 12 and 24.RESULTS: In total, 418 patients were randomized, and baseline characteristics were balanced across the treatment groups. Patients receving clazakizumab had significantly greater ACR20 response rates at week 12 compared with patients receiving MTX alone (76.3%, 73.3%, and 60.0% of patients in the clazakizumab 25, 100, and 200 mg plus MTX groups, respectively, and 55.0% and 61.0% of patients in the clazakizumab 100 and 200 mg monotherapy groups, respectively, versus 39.3% of patients receiving MTX alone; P < 0.05 for all comparisons). At week 24, all clazakizumab groups had higher ACR20, ACR50, and ACR70 response rates and higher remission rates compared with MTX alone. Rates of serious adverse events ranged from 8.3% to 13.6% in the clazakizumab treatment groups, compared with 3.3% in the MTX alone group. Changes in laboratory data were consistent with the pharmacologic effects of IL-6 blockade.CONCLUSION: In patients with RA and an inadequate response to MTX, treatment with clazakizumab in combination with MTX or clazakizumab monotherapy was well tolerated, and patients achieved significant improvements in disease activity, including higher rates of remission, as compared with patients receiving MTX alone.

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Infliximab and etanercept have distinct actions but similar effects on cytokine profiles in rheumatoid arthritis

Takeshita M., Suzuki K., Kikuchi J., Izumi K., Kurasawa T., Yoshimoto K., Amano K., Takeuchi T.

Cytokine （Cytokine） 75 （ 2 ） 222 - 227 2015年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1043-4666

© 2015 Elsevier Ltd. Objective: Pro-inflammatory cytokines, especially TNFα, play a central role in the pathogenesis of rheumatoid arthritis (RA). The available TNF inhibitors are only slightly different from one another in terms of clinical efficacy, at least at the group level, but their structures and modes of action are not identical. Infliximab (IFX) and etanercept (ETN) differ in their ability to induce antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, and in their ability to bind TNFβ. The purpose of our study was to elucidate the different cytokine pathways through which these two drugs enact their clinical efficacy. Methods: Serum from 44 RA patients treated with IFX and 24 patients treated with ETN was studied. All patients had been given these biologics at identical dosages and intervals for one year. The concentrations of 11 inflammatory cytokines and their receptors (IL-1β, IL-2, IL-6, IL-6R, IL-8, IL-10, IL-12, TNFα, TNFβ, IFNγ, and GM-CSF) were measured at weeks 0, 22, and 54 using a high-sensitivity electro-chemiluminescence assay. Cytokine profiles were analyzed along with clinical efficacy. Results: IL-6 was significantly decreased in the ETN. +. MTX and IFX. +. MTX groups, although not in the ETN-only group; this change was consistent with changes in disease activity. IFNγ was gradually increased only in the non-remission subgroup of the IFX group, and not at all in the ETN group. TNFβ increased after starting IFX regardless of clinical efficacy. Conclusion: IL-6 inhibition is a pathway affected by both IFX and ETN. In addition, IFNγ increase is a distinctive feature of the inefficacy of IFX.

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Sustainable Efficacy of Switching from Intravenous to Subcutaneous Tocilizumab Monotherapy in Patients with Rheumatoid Arthritis

Ogata A., Atsumi T., Fukuda T., Hirabayashi Y., Inaba M., Ishiguro N., Kai M., Kawabata D., Kida D., Kohsaka H., Matsumura R., Minota S., Mukai M., Sumida T., Takasugi K., Tamaki S., Takeuchi T., Ueda A., Yamamoto K., Yamanaka H., Yoshifuji H., Nomura A.

Arthritis Care and Research （Arthritis Care and Research） 67 （ 10 ） 1354 - 1362 2015年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2151-464X

© 2015 The Authors. Arthritis Care & Research is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology. Objective To evaluate the efficacy and safety of switching from intravenous (IV) tocilizumab (TCZ) to subcutaneous (SC) TCZ monotherapy in rheumatoid arthritis patients. Methods Patients who had completed 24 weeks of TCZ-SC (162 mg/2 weeks) or TCZ-IV (8 mg/kg/4 weeks) monotherapy in the double-blind period of the MUSASHI study were enrolled in an 84-week open-label extension period. All received TCZ-SC (162 mg/2 weeks) monotherapy. Effects of the IV to SC switch were evaluated at week 36 (12 weeks after switching). Results Overall, 319 patients received ≥1 dose of TCZ-SC during the open-label extension period; 160 switched from TCZ-IV to TCZ-SC (TCZ IV/SC) and 159 continued TCZ-SC (TCZ SC/SC). Disease Activity Score in 28 joints using the erythrocyte sedimentation rate clinical remission rates were 62.5% (100 of 160) for TCZ IV/SC and 50.0% (79 of 158) for TCZ SC/SC at week 24, and were maintained at 62.5% (100 of 160) and 57.0% (90 of 158), respectively, at week 36. In the TCZ IV/SC group, 9% of patients (9 of 100) who had achieved remission at week 24 could not maintain remission at week 36. In TCZ IV/SC patients weighing ≥70 kg, the percentage with a sufficient serum TCZ concentration (≥1 μg/ml) decreased from 90.9% (10 of 11) at week 24 to 45.5% (5 of 11) at week 36. Overall safety profiles were similar in TCZ IV/SC and TCZ SC/SC except for mild injection site reactions in TCZ IV/SC. Conclusion Efficacy is adequately maintained in most patients switching from TCZ-IV (8 mg/kg/4 weeks) to TCZ-SC (162 mg/2 weeks) monotherapy. Patients receiving TCZ-IV can switch to TCZ-SC without serious safety concerns. Clinical efficacy may be reduced after switching in some patients with high body weight.

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Evaluation of the pharmacokinetic equivalence and 54-week efficacy and safety of CT-P13 and innovator infliximab in Japanese patients with rheumatoid arthritis

Takeuchi T., Yamanaka H., Tanaka Y., Sakurai T., Saito K., Ohtsubo H., Lee S., Nambu Y.

Modern Rheumatology （Modern Rheumatology） 25 （ 6 ） 817 - 824 2015年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2015 The Author(s). Published by Japan College of Rheumatology. Objectives. To demonstrate the pharmacokinetic equivalence of CT-P13 and its innovator infliximab (IFX) in Japanese patients with rheumatoid arthritis (RA), and to compare the efficacy and safety of these drugs, administered for 54 weeks. Methods. In a randomized, double-blind, parallel-group, multicenter study, 3 mg/kg of CT-P13 or IFX, in combination with methotrexate (MTX) (6-16 mg/week), was administered for 54 weeks to Japanese active RA patients with an inadequate response to MTX, to demonstrate the pharmacokinetic equivalence, based on the area under the curve (AUCτ) (weeks 6-14) and Cmax (week 6) of these drugs, and to compare their efficacy and safety. Results. The CT-P13-to-IFX ratios (90% confidence intervals) of the geometric mean AUCτ and Cmax values in patients negative for antibodies to infliximab at week 14 were 111.62% (100.24-124.29%) and 104.09% (92.12-117.61%), respectively, demonstrating the pharmacokinetic equivalence of these drugs. In the full analysis set, CT-P13 and IFX showed comparable therapeutic effectiveness, as measured by the American College of Rheumatology, Disease Activity Score in 28 joints, the European League Against Rheumatism, and other efficacy criteria, at weeks 14 and 30. The incidence of adverse events was similar for these drugs. Conclusion. CT-P13 and IFX, administered at a dose of 3 mg/kg in combination with MTX to active RA patients, were pharmacokinetically equivalent and comparable in efficacy and safety.

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Long-term safety and efficacy of treatment with subcutaneous abatacept in Japanese patients with rheumatoid arthritis who are methotrexate inadequate responders

Amano K., Matsubara T., Tanaka T., Inoue H., Iwahashi M., Kanamono T., Nakano T., Uchimura S., Izumihara T., Yamazaki A., Karyekar C., Takeuchi T.

Modern Rheumatology （Modern Rheumatology） 25 （ 5 ） 665 - 671 2015年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2015 Japan College of Rheumatology. Objective. To assess the long-term safety, immunogenicity, and efficacy of subcutaneous (SC) abatacept in combination with methotrexate (MTX) in Japanese patients with rheumatoid arthritis who were MTX inadequate responders, in a long-term extension (LTE) to a double-dummy, double-blind study (NCT01001832). Methods. Patients, who had previously received SC or intravenous (IV) abatacept with MTX (6-8 mg/week) for 24 weeks, received SC abatacept (125 mg/week) with MTX for an additional 52 weeks. Safety, immunogenicity, and efficacy were assessed. Results. The LTE included 112 patients. SC abatacept was generally well tolerated in the LTE, with no new safety signals. American College of Rheumatology 20, 50, and 70 response rates, disease activity score 28 (C-reactive protein) remission rates (< 2.6), and Health Assessment Questionnaire-Disability Index response rates (≥ 0.3 improvement from baseline) achieved at the end of the double-blind period were maintained over the LTE and were comparable in patients who received SC or IV abatacept in the double-blind period. Seropositivity for immunogenicity occurred in 4 (3.6%) patients. Self-injection of SC abatacept was well controlled and not associated with additional safety events. Conclusions. SC abatacept had acceptable safety and was well tolerated and effective over the LTE (76 weeks in total), with low rates of immunogenicity in Japanese patients.

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Early achievement of complete renal response predicts good long-term renal outcome and low systemic damage in newly diagnosed lupus nephritis class III or IV

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

Modern Rheumatology （Modern Rheumatology） 25 （ 5 ） 714 - 718 2015年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2015 Japan College of Rheumatology. Objective. To identify predictors of long-term renal prognosis after induction therapy in patients with newly diagnosed lupus nephritis class III or IV. Methods. We retrospectively studied patients with newly diagnosed lupus nephritis class III or IV. We divided them into two groups according to the complete renal response (CR) status at 3 years after induction therapy. We compared baseline clinical characteristics, renal pathological findings, and time to achieve CR, and identified predictors. Patients were followed up for to 10 years to assess long-term systemic damage. Results. Eighteen patients with CR and 9 with non-CR were included. There were no significant differences in baseline characteristics. Early CR, which was defined as achieving CR at 3 months after induction therapy, was significantly associated with maintaining CR at 3 years (p = 0.012). Patients with early CR less frequently had flare in systemic manifestation compared with those without over 10 years (p = 0.026). Deterioration of systemic damage was observed more often in non-early CR patients than early CR patients at 10 years (p = 0.029). Conclusion. Achieving CR at 3 months after induction therapy may predict CR at 3 years, reduced organ damage, and a low incidence of disease flare for 10 years.

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Glomerulomegaly in lupus nephritis: A prognostic marker for renal outcomes

Hanaoka H., Kuwana M., Takeuchi T.

International Journal of Rheumatic Diseases （International Journal of Rheumatic Diseases） 18 （ 7 ） 768 - 775 2015年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1756-1841

© 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd. Aim: Glomerulomegaly refers to the abnormal enlargement of glomeruli and is associated with an increased risk of progressive chronic kidney disease (CKD). However, it has rarely been investigated in lupus nephritis (LN). We therefore assessed glomerulomegaly as a prognostic factor for renal pathology. Method: Patients with class III or IV LN were retrospectively recruited and divided into two groups according to complete renal response (CR) at 3 years after the initiation of induction therapy. Baseline clinical and renal pathological findings were compared to identify prognostic factors, and patients were followed for up to 10 years to assess long-term renal outcomes. Results: Nineteen patients with and 19 without CR on 3-year follow-up were analyzed. Long-term disease duration and high levels of proteinuria were frequently observed in patients without CR (P = 0.03 and P = 0.01, respectively) at baseline compared to those with CR. On renal pathological analysis, a significantly higher proportion of patients without CR had enlarged glomeruli than those with CR (P = 0.03) in analysis of segmentally or minimally affected glomeruli. On 10-year follow-up, a higher proportion of patients without enlarged glomeruli maintained CR compared to those with enlarged glomeruli (P = 0.004). Further, glomerular area and disease duration were significantly correlated (P = 0.04). Conclusions: Enlarged segmentally or minimally affected glomeruli at diagnosis of LN might predict a worse renal prognosis at 3 years after induction therapy. Mechanical glomerular injury might influence clinical outcomes. International Journal of Rheumatic Diseases

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Number of circulating follicular helper 2 T cells correlates with IgG4 and interleukin-4 levels and plasmablast numbers in IgG4-related disease

Akiyama M., Suzuki K., Yamaoka K., Yasuoka H., Takeshita M., Kaneko Y., Kondo H., Kassai Y., Miyazaki T., Morita R., Yoshimura A., Takeuchi T.

Arthritis and Rheumatology （Arthritis and Rheumatology） 67 （ 9 ） 2476 - 2481 2015年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2326-5191

© 2015, American College of Rheumatology. Objective To elucidate the pathologic role of follicular helper T (Tfh) cells and their subsets in active, untreated IgG4-related disease. Methods Fifteen patients with active, untreated, biopsy-proven IgG4-related disease, 24 patients with primary Sjögren's syndrome (SS), 12 patients with allergic rhinitis, and 23 healthy controls were evaluated. Tfh cells were defined as CD3+CD4+CXCR5+CD45RA- cells. Circulating Tfh cell subsets among CXCR5+CD45RA-CD4+ T cells were defined as Tfh17 cells (CXCR3-CCR6+), Tfh1 cells (CXCR3+CCR6-), or Tfh2 cells (CXCR3-CCR6-). CD19+CD20-CD27+CD38+ cells were defined as plasmablasts. Serum cytokine levels (interleukin-4 [IL-4], IL-10, IL-21, and IL-33) were measured by cytometric bead array or enzyme-linked immunosorbent assay. Results Patients with IgG4-related disease had significantly increased levels of Tfh2 cells compared to healthy controls or patients with primary SS or allergic rhinitis. Increased Tfh2 levels were strongly associated with increased serum IgG4 levels and the IgG4:IgG ratio in IgG4-related disease. A positive correlation was observed between Tfh2 counts, plasmablast counts, and serum IL-4 levels. Interestingly, levels of plasmablasts and serum IL-4 and IgG4 decreased after treatment with glucocorticoids, whereas no obvious change was observed in Tfh2 cell counts. Conclusion The Tfh2 cell count was specifically increased in IgG4-related disease and was correlated with elevated serum levels of IgG4 and IL-4 and plasmablast counts. Tfh2 cells were the only component that was not affected by glucocorticoid treatment, suggesting that Tfh2 cells are the cell type implicated in IgG4-related disease.

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Anti-signal recognition particle antibody in patients without inflammatory myopathy: A survey of 6180 patients with connective tissue diseases

Hanaoka H., Kaneko Y., Suzuki S., Takada T., Hirakata M., Takeuchi T., Kuwana M.

Scandinavian Journal of Rheumatology （Scandinavian Journal of Rheumatology） 45 （ 1 ） 1 - 5 2015年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0300-9742

© 2016 Informa Healthcare on license from Scandinavian Rheumatology Research Foundation. Objectives: To clarify the prevalence of anti-signal recognition particle (anti-SRP) antibody in connective tissue diseases (CTDs) and investigate the clinical characteristics of patients without inflammatory myopathy.Method: Sera from 6180 patients with CTD were examined by immunoprecipitation (IPP) assays, and the records of patients positive for anti-SRP antibody were reviewed retrospectively. The antibody against the 54-kDa protein of SRP (SRP54) was quantified by enzyme-linked immunosorbent assay (ELISA) in patients with anti-SRP antibody.Results: Of the 28 patients positive for anti-SRP antibody, nine (32.1%) did not have inflammatory myopathy. The clinical diagnoses and characteristics of those patients varied considerably. In patients with inflammatory myopathy, the index of anti-SRP54 was much higher than in those without myopathy (1.15 vs. 0.46; p = 0.036).Conclusions: The prevalence of anti-SRP antibody was 0.5% in a cohort of Japanese patients with CTD, and one-third of them did not have inflammatory myopathy. Sera from patients with inflammatory myopathy recognized SRP54 more strongly than in those without myopathy.

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Brief report: Leucine-rich α<inf>2</inf>-glycoprotein as a potential biomarker for joint inflammation during anti-interleukin-6 biologic therapy in rheumatoid arthritis

Fujimoto M., Serada S., Suzuki K., Nishikawa A., Ogata A., Nanki T., Hattori K., Kohsaka H., Miyasaka N., Takeuchi T., Naka T.

Arthritis and Rheumatology （Arthritis and Rheumatology） 67 （ 8 ） 2056 - 2060 2015年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2326-5191

© 2015, American College of Rheumatology. Objective To investigate whether leucine-rich α<inf>2</inf>-glycoprotein (LRG) could be a biomarker for disease activity during interleukin-6 (IL-6) blockade treatment of rheumatoid arthritis (RA). Methods In 59 RA patients who were treated with tocilizumab for 24 weeks, serum LRG levels were determined by enzyme-linked immunosorbent assay. RA disease activity was evaluated by the Clinical Disease Activity Index (CDAI). Receiver operating characteristic (ROC) curve analysis was used to examine the diagnostic performance of LRG and other biomarkers. In monkeys with experimental autoimmune arthritis, swollen joint counts, joint pathologic changes, and blood levels of C-reactive protein (CRP) and LRG were evaluated after treatment with anti-IL-6 receptor antibody. Results Among tocilizumab-treated RA patients, those with active disease (CDAI >2.8) had significantly higher serum LRG levels compared to those whose disease was in remission. ROC curve analysis suggested that the LRG level was more useful than the CRP or matrix metalloproteinase 3 level or the erythrocyte sedimentation rate in discriminating between remission and active disease during therapy with tocilizumab. In monkeys treated with IL-6 blockade, joint scores were more closely correlated with LRG levels than with CRP levels. Histologic analysis of joints revealed that LRG levels correlated significantly with granulomatous tissue formation, cartilage degeneration, and bone destruction in IL-6 blockade-treated monkeys with low levels of CRP. Conclusion Under conditions of IL-6 inhibition, LRG was more useful than other biomarkers in discriminating between active and inactive disease in human RA and in detecting joint inflammation in experimental arthritis. LRG may serve as a convenient biomarker for RA disease activity during IL-6 blockade treatment.

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Crohn’s disease in which the patient developed aortitis during treatment with adalimumab

Kiyohara H., Hisamatsu T., Matsuoka K., Naganuma M., Kameda H., Seta N., Takeuchi T., Kanai T.

Internal Medicine （Internal Medicine） 54 （ 14 ） 1725 - 1732 2015年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0918-2918

© 2015 The Japanese Society of Internal Medicine. A 23-year-old woman developed aortitis during treatment with adalimumab (ADA) for ileocolic Crohn’s disease (CD). The patient complained of a high fever, abdominal pain, diarrhea, hematochezia and arthralgia. Although the ADA therapy resulted in immediate symptom improvement, after six weeks, she again complained of a low-grade fever and abdominal pain, whereas the CD-related symptoms did not worsen. Contrast-enhanced computed tomography revealed thoracoabdominal aortitis, and we therefore started treatment with prednisolone, which immediately improved the fever and abdominal pain. We subsequently tapered the dose of prednisolone and resumed the administration of ADA in order to maintain the CD remission. No further episodes of aortitis relapse were noted after restarting ADA, and the CD currently remains in remission. This is the first report of the onset of aortitis during ADA therapy for CD.

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Polarization diversity of human CD4+ stem cell memory T cells

Takeshita M., Suzuki K., Kassai Y., Takiguchi M., Nakayama Y., Otomo Y., Morita R., Miyazaki T., Yoshimura A., Takeuchi T.

Clinical Immunology （Clinical Immunology） 159 （ 1 ） 107 - 117 2015年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1521-6616

© 2015 Elsevier Inc. T cells are considered to develop through three stages, from naïve T (Tn) into central memory T (Tcm) and finally into effector memory T (Tem). Among the subsets of Tn, stem cell memory T (Tscm) were recently found to be the least developed memory subset. While this subset was revealed to possess self-reproducibility and multipotentiality, little is known about the relationship between development and polarity. We conducted transcriptome analysis of human CD4+ T subsets and found that Tscm was a clearly distinct subset, located between Tn and Tcm. Surface antigen analysis and differentiation assay showed that the flexibility of polarity and the cytokine production progressively changed as the differentiation of CD4+ T cells advanced. Interestingly, we found that most cells of the CD45RO-CCR7+CCR6+ subset, hitherto considered the naïve precursor of Th17, were in fact Tscm. These findings may advance our understanding of the highly heterogeneous human helper T cells.

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Trend of patient characteristics and its impact on the response to adalimumab in patients with rheumatoid arthritis: Post hoc time-course analysis of an all-case pms in Japan

Yamanaka H., Harigai M., Ishiguro N., Inokuma S., Takei S., Takeuchi T., Tanaka Y., Suzuki H., Shinmura Y., Koike T.

Modern Rheumatology （Modern Rheumatology） 25 （ 4 ） 495 - 502 2015年07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 investigate the relationship between changes in patient characteristics over time and the eff ectiveness and safety of adalimumab in the treatment of rheumatoid arthritis (RA) in clinical practice. Methods. Patients enrolled in the post-marketing registry study in Japan were divided into 5 subgroups based on the time adalimumab treatment was initiated. Demographic and baseline characteristics and responses to adalimumab were compared among the 5 subgroups to detect any time-course trend. Multiple logistic regression analysis was performed to identify characteristics that were signifi cantly associated with the eff ectiveness or safety of adalimumab and to estimate response rates and the incidence of adverse drug reactions in individual subgroups. Results. During the study period, patient characteristics changed signifi cantly over time, in particular with regard to prior biologic use and concomitant methotrexate therapy. There was a signifi cant trend toward higher response rates and lower incidence of infections and injection-site reactions in patients initiating adalimumab later in the study. Patient characteristics, such as concomitant methotrexate therapy and early stage RA, were signifi cant predictors of the eff ectiveness and safety of adalimumab. Conclusions. Patient characteristics have changed since adalimumab became available for the treatment of RA; several of these characteristics were signifi cant predictors of adalimumab eff ectiveness and safety.

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Effi cacy and safety of tofacitinib as monotherapy in japanese patients with active rheumatoid arthritis: A 12-week, randomized, phase 2 study

Tanaka Y., Takeuchi T., Yamanaka H., Nakamura H., Toyoizumi S., Zwillich S.

Modern Rheumatology （Modern Rheumatology） 25 （ 4 ） 514 - 521 2015年07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 evaluate oral tofacitinib versus placebo for treatment of active rheumatoid arthritis in Japanese patients with inadequate response to disease-modifying antirheumatic drugs. Methods. In this double-blind, placebo-controlled, randomized, parallel-group, 12-week, phase 2 study (clinicaltrials.gov NCT00687193), 317 patients received tofacitinib: 1, 3, 5, 10, or 15 mg as monotherapy or placebo twice daily (BID). Primary endpoint: response rate by American College of Rheumatology (ACR) > 20% improvement criteria (ACR20) at week 12. Results. ACR20 response rates: 37.7% (20/53), 67.9% (36/53), 73.1% (38/52), 84.9% (45/53), and 90.7% (49/54) with tofacitinib: 1, 3, 5, 10, and 15 mg BID, respectively, versus 15.4% (8/52) with placebo (p<0.01; all doses). Dose-dependent ACR20 responses with tofacitinib versus placebo occurred from week 2 onward (p< 0.05). Changes from baseline in 28-joint disease activity score using erythrocyte sedimentation rate improved with tofacitinib versus placebo from week 4 (p < 0.01; all doses). Six tofacitinib patients experienced treatment-related serious adverse events (AEs). Most common treatment-emergent AEs: nasopharyngitis (10% vs 12%) and hyperlipidemia (5% vs 0%). Serum creatinine, hemoglobin, and total-, low-, and high-density lipoprotein-choles-terol levels increased with tofacitinib. Conclusions. Tofacitinib produced dose-dependent ACR20 responses and reduced disease activity. The safety profi le was consistent with that reported from global monotherapy trials.

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Acute kidney injury due to renal sarcoidosis during etanercept therapy: A case report and literature review

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

Internal Medicine （Internal Medicine） 54 （ 9 ） 1131 - 1134 2015年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0918-2918

© 2015 The Japanese Society of Internal Medicine. We herein report a case of renal sarcoidosis presenting as acute kidney injury (AKI) during treatment with etanercept for rheumatoid arthritis. Blood tests showed a high level of angiotensin-converting enzyme and a renal biopsy demonstrated non-caseating granulomatous tubulointerstitial nephritis. The administration of high-dose steroid therapy (1 mg/kg) and discontinuation of etanercept resulted in an improvement in the patient’s renal function. Although renal sarcoidosis induced by anti-tumor necrosis factor (TNF) therapy is an extremely rare manifestation, this case suggests that renal sarcoidosis should be considered in the differential diagnosis of AKI in patients receiving anti-TNF therapy, as providing an early diagnosis and treatment is important for preventing irreversible renal impairment.

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The effect of tocilizumab on preventing relapses in adult-onset still's disease: A retrospective, single-center study

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

Modern Rheumatology （Modern Rheumatology） 25 （ 3 ） 401 - 404 2015年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2014 Japan College of Rheumatology. Objectives. To investigate the clinical effectiveness of tocilizumab (TCZ), a monoclonal antibody against the interleukin-6 receptor, in preventing relapse in patients with adult-onset Still's disease (AOSD). Methods. This retrospective study included clinical data from 40 patients who underwent regular follow-up at our institution in June 2013. Among these patients, 10 received TCZ. The relapse-free rate was analyzed by the Kaplan-Meier method. Results. The age at disease onset (median, interquartile range [IQR]) was 39 (29-52) years. The duration of disease in June 2013 (median, IQR) was 86 (41-193) months. A total of 87 relapses were documented in 27 patients. Ten patients with refractory or relapsing disease received 8 mg/kg of TCZ every 2-4 weeks. After 6 months of TCZ treatment, the median levels of C-reactive protein significantly decreased from 6.3 to 0.01 mg/dl (p < 0.01). Among these 10 patients, 11 relapses were observed before TCZ treatment, and none were observed after the treatment. The relapse-free rate of the 10 patients after starting TCZ was significantly higher than that of all 40 patients after the initial treatments (100% and 67% at 12 months, respectively; p = 0.03). Conclusions.TCZ effectively prevented relapses of AOSD, and it resolved the disease activity.

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Anti-citrullinated peptide/protein antibody (ACPA)-negative RA shares a large proportion of susceptibility loci with ACPA-positive RA: A meta-analysis of genome-wide association study in a Japanese population

Terao C., Ohmura K., Kochi Y., Ikari K., Okada Y., Shimizu M., Nishina N., Suzuki A., Myouzen K., Kawaguchi T., Takahashi M., Takasugi K., Murasawa A., Mizuki S., Iwahashi M., Funahashi K., Natsumeda M., Furu M., Hashimoto M., Ito H., Fujii T., Ezawa K., Matsubara T., Takeuchi T., Kubo M., Yamada R., Taniguchi A., Yamanaka H., Momohara S., Yamamoto K., Mimori T., Matsuda F.

Arthritis Research and Therapy （Arthritis Research and Therapy） 17 （ 1 ） 2015年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1478-6354

© Terao et al.; licensee BioMed Central. Introduction: Although susceptibility genes for anti-citrullinated peptide/protein antibodies (ACPA)-positive rheumatoid arthritis (RA) have been successfully discovered by genome-wide association studies (GWAS), little is known about the genetic background of ACPA-negative RA. We intended to elucidate genetic background of ACPA-negative RA. Method: We performed a meta-analysis of GWAS comprising 670 ACPA-negative RA and 16,891 controls for 1,948,138 markers, followed by a replication study of the top 35 single nucleotide polymorphisms (SNPs) using 916 cases and 3,764 controls. Inverse-variance method was applied to assess overall effects. To assess overlap of susceptibility loci between ACPA-positive and -negative RA, odds ratios (ORs) of the 21 susceptibility markers to RA in Japanese were compared between the two subsets. In addition, SNPs were stratified by the p-values in GWAS meta-analysis for either ACPA-positive RA or ACPA-negative RA to address the question whether weakly-associated genes were also shared. The correlations between ACPA-positive RA and the subpopulations of ACPA-negative RA (rheumatoid factor (RF)-positive and RF-negative subsets) were also addressed. Results: Rs6904716 in LEMD2 of the human leukocyte antigen (HLA) locus showed a borderline association with ACPA-negative RA (overall p = 5.7 × 10-8), followed by rs6986423 in CSMD1 (p = 2.4 × 10-6) and rs17727339 in FCRL3 (p = 1.4 × 10-5). ACPA-negative RA showed significant correlations of ORs with ACPA-positive RA for the 21 susceptibility SNPs and non-HLA SNPs with p-values far from significance. These significant correlations with ACPA-positive RA were true for ACPA-negative RF-positive and ACPA-negative RF-negative RA. On the contrary, positive correlations were not observed between the ACPA-negative two subpopulations. Conclusion: Many of the susceptibility loci were shared between ACPA-positive and -negative RA.

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Prediction of clinical response after 1 year of infliximab therapy in rheumatoid arthritis based on disease activity at 3 months: Posthoc analysis of the RISING study

Takeuchi T., Miyasaka N., Inui T., Yano T., Yoshinari T., Abe T., Koike T.

Journal of Rheumatology （Journal of Rheumatology） 42 （ 4 ） 599 - 607 2015年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

Objective. To investigate the probability of clinical remission (REM) or low disease activity (LDA) after 1 year of infliximab (IFX) therapy based on disease activity at 3 months in patients with rheumatoid arthritis (RA). Methods. Methotrexate-refractory patients with RA received 3 mg/kg of IFX at weeks 0, 2, and 6, followed by 3 mg/kg, 6 mg/kg, or 10 mg/kg every 8 weeks from Week 14 (W14) to Week 46. Correlation of disease activity at W14 with disease activity at W54 and probability of REM/LDA at W54 were analyzed in each dosing group. Results. Disease activities at W14 were significantly correlated with both disease activity at W54 and probability of REM/LDA at W54 in patients continuing 3 mg/kg as well as in those receiving 6 mg/kg or 10 mg/kg therapy from W14. Results showed that, if approximate REM or LDA had not been achieved by W14, ≥ 50% of patients continuing 3 mg/kg therapy would not be able to achieve REMor LDAatW54. However, even in patients with high or moderate disease activity atW14, dose escalation to 6 mg/kg or 10 mg/kg enabled many to achieve REM/LDA. Conclusion. Disease activity at W14 in standard-dose IFX therapy enabled the prediction of longterm clinical response at continued standard dose, as well as subsequent escalated-dose regimens. Disease activity at W14 was hypothesized to be an important index for IFX treatment strategy.

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Head-to-head comparison of the safety of tocilizumab and tumor necrosis factor inhibitors in rheumatoid arthritis patients (RA) in clinical practice: Results from the registry of Japanese RA patients on biologics for long-term safety (REAL) registry

Sakai R., Cho S., Nanki T., Watanabe K., Yamazaki H., Tanaka M., Koike R., Tanaka Y., Saito K., Hirata S., Amano K., Nagasawa H., Sumida T., Hayashi T., Sugihara T., Dobashi H., Yasuda S., Sawada T., Ezawa K., Ueda A., Fujii T., Migita K., Miyasaka N., Harigai M., Atsumi T., Ishigatsubo Y., Ihata A., Mimori T., Takasaki Y., Tamura N., Hashiramoto A., Shiozawa S., Kameda H., Kaneko Y., Takeuchi T., Ochi S., Miura Y., Nonomura Y., Nakajima A., Michishita K., Yamamoto K., Ueki Y., Nagasaka K., Okada A., Kawakami A., Tohma S., Nakajima A., Yamanaka H.

Arthritis Research and Therapy （Arthritis Research and Therapy） 17 （ 1 ） 2015年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1478-6354

© Sakai et al. Introduction: The objective of this study was to directly compare the safety of tocilizumab (TCZ) and TNF inhibitors (TNFIs) in rheumatoid arthritis (RA) patients in clinical practice. Methods: This prospective cohort study included RA patients starting TCZ [TCZ group, n = 302, 224.68 patient-years (PY)] or TNFIs [TNFI group, n = 304, 231.01 PY] from 2008 to 2011 in the registry of Japanese RA patients on biologics for long-term safety registry. We assessed types and incidence rates (IRs) of serious adverse events (SAEs) and serious infections (SIs) during the first year of treatment. Risks of the biologics for SAEs or SIs were calculated using the Cox regression hazard analysis. Results: Patients in the TCZ group had longer disease duration (P <0.001), higher disease activity (P = 0.019) and more frequently used concomitant corticosteroids (P <0.001) than those in the TNFI group. The crude IR (/100 PY) of SIs [TCZ 10.68 vs. TNFI 3.03; IR ratio (95% confidence interval [CI]), 3.53 (1.52 to 8.18)], but not SAEs [21.36 vs. 14.72; 1.45 (0.94 to 2.25)], was significantly higher in the TCZ group compared with the TNFI group. However, after adjusting for covariates using the Cox regression hazard analysis, treatment with TCZ was not associated with higher risk for SAEs [hazard ratio (HR) 1.28, 95% CI 0.75 to 2.19] or SIs (HR 2.23, 95% CI 0.93 to 5.37). Conclusions: The adjusted risks for SAEs and SIs were not significantly different between TCZ and TNFIs, indicating an influence of clinical characteristics of the patients on the safety profile of the biologics in clinical practice.

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Pharmacokinetics, efficacy and safety profiles of etanercept monotherapy in Japanese patients with rheumatoid arthritis: Review of seven clinical trials

Takeuchi T., Miyasaka N., Kawai S., Sugiyama N., Yuasa H., Yamashita N., Sugiyama N., Wagerle L., Vlahos B., Wajdula J.

Modern Rheumatology （Modern Rheumatology） 25 （ 2 ） 173 - 186 2015年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Ó 2014 Japan College of Rheumatology. Conventional synthetic disease-modifying anti-rheumatic drugs, including methotrexate, may not be tolerated by all patients with rheumatoid arthritis (RA), and limited international data for etanercept (ETN) monotherapy are available. The aim of this review was to summarize the clinical program for ETN monotherapy in Japanese patients with RA, which has included a pharmacokinetic study, clinical trials for registration, long-term studies, and once-weekly dosing studies. Pharmacokinetic results showed that serum concentrations of ETN were linear with dose levels and were similar to other international studies. Across interventional studies, 652 Japanese patients with active RA were treated with ETN. In the registration studies, ETN treatment led to consistent improvement in American College of Rheumatology 20/50/70 scores, European League Against Rheumatism Good Response, Disease Activity Score 28 erythrocyte sedimentation rate remission, and Health Assessment Questionnaire disability index. In the long-term studies, efficacy was maintained for up to 180 weeks. Similar results were seen in the once-weekly studies. Across the studies, more than 870 patient-years of exposure to ETN were recorded. Discontinuations owing to lack of efficacy or adverse events were modest and no new safety signals were recorded. These studies demonstrated that ETN monotherapy is efficacious and well-tolerated in Japanese patients with RA.

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Proteomic identification of heterogeneous nuclear ribonucleoprotein K as a novel cold-associated autoantigen in patients with secondary Raynaud's phenomenon

Yang L., Fujimoto M., Murota H., Serada S., Fujimoto M., Honda H., Yamada K., Suzuki K., Nishikawa A., Hosono Y., Yoneda Y., Takehara K., Imura Y., Mimori T., Takeuchi T., Katayama I., Naka T.

Rheumatology (United Kingdom) （Rheumatology (United Kingdom)） 54 （ 2 ） 349 - 358 2015年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1462-0324

© The Author 2014. Objective. The aim of this study was to identify cold-associated autoantibodies in patients with RP secondary to CTDs. Methods. Indirect immunofluorescence staining was performed on non-permeabilized cold-stimulated normal human dermal microvascular endothelial cells (dHMVECs), using patients' sera. Cold-induced alterations in cell surface proteomes were analysed by isobaric tag for relative and absolute quantitation (iTRAQ) analysis. Serological proteome analysis (SERPA) was applied to screen cold-associated autoantigens. The prevalence of the candidate autoantibody was determined by ELISA in 290 patients with RP secondary to CTDs (SSc, SLE or MCTD), 10 patients with primary RP and 27 healthy controls. Results. Enhanced cell surface immunoreactivity was detected in cold-stimulated dHMVECs when incubated with sera from patients with secondary RP. By iTRAQ analysis, many proteins, including heterogeneous nuclear ribonucleoprotein K (hnRNP-K), were found to be increased on the cell surface of dHMVECs after cold stimulation. By the SERPA approach, hnRNP-K was identified as a candidate autoantigen in patients with secondary RP. Cold-induced translocation of hnRNP-K to the cell surface was confirmed by immunoblotting and flow cytometry. By ELISA analysis, patients with secondary RP show a significantly higher prevalence of anti-hnRNP-K autoantibody (30.0%, 61/203) than patients without RP (9.2%, 8/87, P = 0.0001), patients with primary RP (0%, 0/10, P = 0.0314) or healthy controls (0%, 0/27, P = 0.0001). Conclusion. By comprehensive proteomics, we identified hnRNP-K as a novel cold-associated autoantigen in patients with secondary RP. Anti-hnRNP-K autoantibody may potentially serve as a biomarker for RP secondary to various CTDs.

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Elevated levels of pentraxin 3 in systemic sclerosis: Associations with vascular manifestations and defective vasculogenesis

Shirai Y., Okazaki Y., Inoue Y., Tamura Y., Yasuoka H., Takeuchi T., Kuwana M.

Arthritis and Rheumatology （Arthritis and Rheumatology） 67 （ 2 ） 498 - 507 2015年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2326-5191

Copyright © 2015 by the American College of Rheumatology. Objective. To clarify the role of pentraxin 3 (PTX3), a multifunctional pattern recognition protein that can suppress fibroblast growth factor 2 (FGF-2), in systemic sclerosis (SSc)-related vasculopathy. Methods. We assessed 171 SSc patients and 19 age- and sex-matched healthy control subjects. Circulating PTX3 and FGF-2 levels were measured by enzyme immunoassay, and CD34+CD133+CD309+ endothelial progenitor cells (EPCs) were counted by flow cytometry. Correlations between PTX3 and FGF-2 and the presence or future development of vascular manifestations, including digital ulcers and pulmonary arterial hypertension (PAH), were identified by univariate and multivariate analysis. The effect of PTX3 on EPC differentiation was evaluated in proangiogenic cultures of mouse bone marrow cells in combination with colony formation assay. Results. Circulating PTX3 and FGF-2 levels were significantly higher in SSc patients than in healthy control subjects. PTX3 was elevated in SSc patients who had digital ulcers or PAH, while FGF-2 was reduced in SSc patients with PAH. Multivariate analysis identified elevated PTX3 as an independent parameter associated with the presence of digital ulcers and PAH, and PTX3 levels were a useful predictor of future occurrences of digital ulcers. Reduced FGF-2 was independently associated with the presence of PAH. EPC counts were significantly lower in patients with digital ulcers or PAH and correlated negatively with circulating PTX3 concentrations. Finally, PTX3 inhibited EPC differentiation in vitro. Conclusion. In SSc patients, exposure to high concentrations of PTX3 may suppress EPC-mediated vasculogenesis and promote vascular manifestations such as digital ulcers and PAH.

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Obstacles to the implementation of the treat-to-target strategy for rheumatoid arthritis in clinical practice in Japan

Kaneko Y., Koike T., Oda H., Yamamoto K., Miyasaka N., Harigai M., Yamanaka H., Ishiguro N., Tanaka Y., Takeuchi T.

Modern Rheumatology （Modern Rheumatology） 25 （ 1 ） 43 - 49 2015年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2014 Japan College of Rheumatology. Objective. To clarify the obstacles preventing the implementation of the treat-to-target (T2T) strategy for rheumatoid arthritis (RA) in clinical practice. Methods. A total of 301 rheumatologists in Japan completed a questionnaire. In the fi rst section, participants were indirectly questioned on the implementation of basic components of T2T, and in the second section, participants were directly questioned on their level of agreement and application. Results. Although nearly all participants set treatment targets for the majority of RA patients with moderate to high disease activity, the proportion who set clinical remission as their target was 59%, with only 45% of these using composite measures. The proportion of participants who monitored X-rays and Health Assessment Questionnaires for all their patients was 44% and 14%, respectively. The proportion of participants who did not discuss treatment strategies was 44%, with approximately half of these reasoning that this was due to a proportion of patients having a lack of understanding of the treatment strategy or inability to make decisions. When participants were directly questioned, there was a high level of agreement with the T2T recommendations. Conclusion. Although there was a high level of agreement with the T2T recommendations, major obstacles preventing its full implementation still remain.

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Tocilizumab is clinically, functionally, and radiographically effective and safe either with or without low-dose methotrexate in active rheumatoid arthritis patients with inadequate responses to DMARDs and/or TNF inhibitors: A single-center retrospective cohort study (KEIO-TCZ study) at week 52

Izumi K., Kaneko Y., Yasuoka H., Seta N., Kameda H., Kuwana M., Takeuchi T.

Modern Rheumatology （Modern Rheumatology） 25 （ 1 ） 2015年01月

研究論文（国際会議プロシーディングス）, 共著, 査読有り, ISSN 1439-7595

© 2015, Taylor and Francis Ltd. All rights reserved. Objectives. To explore the effectiveness and safety of tocilizumab (TCZ) with or without methotrexate (MTX) in active rheumatoid arthritis (RA) patients showing inadequate responses to DMARDs and/or TNF inhibitors in clinical practice. Methods. We observed consecutive 115 RA patients initiating TCZ treatment in Keio University Hospital, dividing them into two groups with (TCZ + MTX group) or without MTX (TCZ group), and evaluated clinical, functional and structural outcomes besides safety at week 52. Results. Overall mean age, RA duration, and DAS28-ESR were 55.4, 8.4 years, and 5.0, respectively. Proportions of the prior use of TNF inhibitors and concomitant MTX were 45.5% and 57.4%, respectively. Mean dose of concomitant MTX was 8.4 mg/week. Baseline characteristics were comparable between the groups. TCZ improved disease activity measured by DAS28-ESR to 2.1 at week 52 overall, without significant difference between the groups. Clinical (DAS28-ESR < 2.6),functional (HAQ-DI =£0.5), and structural (ATSS<0.5) remission ratesintheTCZgroupand the TCZ + MTX group were 79.1%/63.8% (P = 0.10), 62.8%/54.4% (P = 0.40), and 70.0%/53.8% (P = 0.61), respectively. Retention rates were 81.0% in the TCZ + MTX group and 88.5% in the TCZ group (P = 0.47. The rate of serious adverse events was comparable between the groups. Conclusions. TCZ was clinically, functionally, and radiographically effective and safe either with or without low-dose MTX.

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Efficacy and safety of mavrilimumab in Japanese subjects with rheumatoid arthritis: Findings from a phase iia study

Takeuchi T., Tanaka Y., Close D., Godwood A., Wu C., Saurigny D.

Modern Rheumatology （Modern Rheumatology） 25 （ 1 ） 21 - 30 2015年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2014 Japan College of Rheumatology. Objective. A phase IIa study investigated efficacy and safety/tolerability of ascending doses of mavrilimumab (anti-granulocyte-macrophage colony-stimulating factor receptor [GM-CSFR] α monoclonal antibody) in adult subjects with moderate to severe rheumatoid arthritis from Japan and Europe. Findings from the Japanese population are presented. Methods. Fifty-one subjects received mavrilimumab (10-100 mg) or placebo subcutaneously every other week for 12 weeks, followed by a 12-week follow-up period. The primary endpoint was the proportion of subjects achieving a Disease Activity Score using 28 joints (DAS28)-Creactive protein (CRP) response (decrease > 1.2 from baseline). Secondary endpoints included DAS28-CRP remission, Health Assessment Questionnaire Disability Index (HAQ-DI) and American College of Rheumatology (ACR) response. Results. By Week 12, more mavrilimumab- versus placebo-treated subjects achieved a DAS28-CRP response (50.0% vs. 23.5%, p = 0.081); a signifi cant response was seen in the 30 mg and 100 mg dose groups (both 75.0% vs. 23.5%, p = 0.028). The 100 mg group also demonstrated statistically signifi cant HAQ-DI and ACR20 responses at Week 12. Results were generally consistent between Japanese and European populations. Overall, adverse events (AEs) were mild to moderate in intensity with one serious AE of pneumonia, considered possibly treatment-related. Conclusions. A rapid and clinically meaningful response was seen in subjects treated with GM-CSFR α blockade with mavrilimumab, supporting further investigation of mavrilimumab for the treatment of RA in Japanese subjects.

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Tocilizumab is effective against polymyalgia rheumatica: Experience in 13 intractable cases

Izumi K., Kuda H., Ushikubo M., Kuwana M., Takeuchi T., Oshima H.

RMD Open （RMD Open） 1 （ 1 ） e000162 2015年

研究論文（学術雑誌）, 共著, 査読有り

Polymyalgia rheumatica (PMR) affects older people, and although glucocorticoids are effective in treating PMR, they frequently result in side effects. Therefore, we conducted a retrospective study to assess the effectiveness and safety of tocilizumab as an alternative to glucocorticoids. We included 13 consecutive patients with PMR (11 women and 2 men; median age, 74 years) diagnosed according to Bird's criteria and the 2012 European League Against Rheumatism/ American College of Rheumatology provisional classification criteria. All patients received tocilizumab infusion (8 mg/kg every 4 weeks) at our institutions, between 2008 and 2014, because of PMR relapses (n=12) or insufficient response to initial prednisolone treatment (n=1), without increasing prednisolone dosage. Seven patients were on methotrexate, and all had one or more glucocorticoid-related comorbidities. Administration of tocilizumab significantly improved inflammation and PMR symptoms such as morning stiffness, as well as the Patient-Pain and Patient-Global Assessment visual analogue scales ( p<0.05). Proximal muscle pain disappeared within 8 weeks, on average, and the Health Assessment Questionnaire-Disability Index scores (p=0.098) and concomitant prednisolone doses (p<0.05) decreased at 12 weeks. Severe adverse events were not observed during the mean tocilizumab treatment period of 43.4 weeks. Our findings suggest that tocilizumab is effective and safe for PMR treatment.

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Peripheral blood CD4+CD25+CD127low regulatory T cells are significantly increased by tocilizumab treatment in patients with rheumatoid arthritis: Increase in regulatory T cells correlates with clinical response

Kikuchi J., Hashizume M., Kaneko Y., Yoshimoto K., Nishina N., Takeuchi T.

Arthritis Research and Therapy （Arthritis Research and Therapy） 17 （ 1 ） R10 2015年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1478-6354

© 2015 Kikuchi et al. Tocilizumab (TCZ), an anti-interleukin-6 receptor antibody, is clinically effective against rheumatoid arthritis (RA), and several reports have indicated how TCZ influences a number of mechanisms underlying RA pathogenesis. However, it is still unclear whether TCZ affects inflammatory cells in peripheral blood and whether any such changes are associated with clinical response. We evaluated associations between proportions of subsets of peripheral immune cells and clinical response in patients with RA treated with TCZ. Methods: Thirty-nine consecutive patients with RA who started to receive TCZ as their first biologic between March 2010 and April 2012 were enrolled. The proportions of several subsets of peripheral cells with their levels of expression of differentiation markers, activation markers and costimulatory molecules were measured sequentially from baseline to week 52 by flow cytometry analysis. Results: Clinical Disease Activity Index (CDAI) remission was achieved in 53.8% of patients at week 52 of TCZ therapy. The proportions of CD4+CD25+CD127low regulatory T cells (Treg) and HLA-DR+ activated Treg cells significantly increased with TCZ therapy (P<0.001 and P<0.001, respectively), whereas proportions of CD3+CD4+CXCR3-CCR6+CD161+ T helper 17 cells did not change over the 52weeks. The proportions of CD20+CD27+ memory B cells, HLA-DR+CD14+ and CD69+CD14+ activated monocytes, and CD16+CD14+ monocytes significantly decreased (P<0.001, P<0.001, P<0.001 and P<0.001, respectively). Among them, only the change in Treg cells was inversely correlated with the change in CDAI score (ρ=-0.40, P=0.011). The most dynamic increase in Treg cells was observed in the CDAI remission group (P<0.001). Conclusion: This study demonstrates that TCZ affected proportions of circulating immune cells in patients with RA. The proportion of Treg cells among CD4+ cells correlated well with clinical response.

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Subclinical labial salivary gland involvement in IgG4-related disease affected with vital organs

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

Clinical and Experimental Rheumatology 33 （ 6 ） 949 - 950 2015年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0392-856X

Overexpression of CXCR4 on circulating B cells in patients with active systemic lupus erythematosus

Hanaoka H., Okazaki Y., Hashiguchi A., Yasuoka H., Takeuchi T., Kuwana M.

Clinical and Experimental Rheumatology （Clinical and Experimental Rheumatology） 33 （ 6 ） 863 - 870 2015年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0392-856X

© Clinical and Experimental Rheumatology 2015. Objective: To evaluate the roles of circulating B cells in the pathogenic process of systemic lupus erythematosus (SLE) by measuring the expression of chemokines and their receptors. Methods: Peripheral-blood mononuclear cells were obtained from 17 active, 21 inactive SLE patients, and 13 healthy controls. The expression of CXCR4, CXCR5, and CCR7 on CD19+ B cells was determined by flow cytometry, serum concentration of CXCL12 was measured by enzyme-linked immunosorbent assay, and the chemotactic responsiveness of B cells toward CXCL12 was evaluated. B or plasma cells expressing CXCR4 in renal biopsy specimens were detected using immnofluorescent staining. Results: Flow cytometric analysis revealed that expression level of CXCR4 on circulating B cells was significantly higher in patients with active disease than in those with inactive disease or controls. Serum CXCL12 concentration was not different between these groups. In addition, the migratory ability of B cells toward CXCL12 was enhanced in active SLE patients. Finally, CXCR4-expressing B cells were more frequently observed in the renal biopsy specimens of lupus nephritis. Conclusion: Up-regulated CXCR4 expression on circulating B cells in active SLE may enhance their chemotactic response toward CXCL12, which may promote infiltration of these cells into inflamed renal tissue and contribute to the development of SLE.

Biologic-free remission of established rheumatoid arthritis after discontinuation of abatacept: A prospective, multicentre, observational study in Japan

Takeuchi T., Matsubara T., Ohta S., Mukai M., Amano K., Tohma S., Tanaka Y., Yamanaka H., Miyasaka N.

Rheumatology (United Kingdom) （Rheumatology (United Kingdom)） 54 （ 4 ） 683 - 691 2014年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1462-0324

© The Author 2014. Objective. The aim of this study was to determine whether biologic-free remission of RA is possible with discontinuation of abatacept. Methods. Japanese RA patients in 28-joint DAS with CRP (DAS28-CRP) remission (<2.3) after >2 years of abatacept treatment in a phase II study and its long-term extension entered this 52 week, multicentre, non-blinded, prospective, observational study. At enrolment, the patients were offered the option to continue abatacept or not. The primary endpoint was the proportion of patients who remained biologic-free at 52 weeks after discontinuation. Clinical, functional and structural outcomes were compared between those who continued and those who discontinued abatacept. Results. Of 51 patients enrolled, 34 discontinued and 17 continued abatacept treatment. After 52 weeks, 22 of the 34 patients (64.7%) remained biologic-free. Compared with the continuation group, the discontinuation group had a similar remission rate (41.2% vs 64.7%, P = 0.144) although they had a significantly higher mean DAS28-CRP score at week 52 (2.9 vs 2.0, P = 0.012). The two groups were also similar with regard to mean HAQ Disability Index (HAQ-DI) score (0.6 for both, P = 0.920), mean change in total Sharp score (ΔTSS; 0.80 vs 0.32, P = 0.374) and proportion of patients in radiographic remission (ΔTSS≤0.5) at the endpoint (64.3% vs 70.6%, P = 0.752). Those attaining DAS28-CRP<2.3 or<2.7 without abatacept at the endpoint had significantly lower HAQ-DI score and/or CRP at enrolment. Non-serious adverse events occurred in three patients who continued or resumed abatacept. Conclusion. Biologic-free remission of RA is possible in some patients after attaining clinical remission with abatacept. Lower baseline HAQ-DI or CRP may predict maintenance of remission or low disease activity after discontinuation of abatacept.

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Efficacy, safety, pharmacokinetics and immunogenicity of abatacept administered subcutaneously or intravenously in Japanese patients with rheumatoid arthritis and inadequate response to methotrexate: A Phase II/III, randomized study

Iwahashi M., Inoue H., Matsubara T., Tanaka T., Amano K., Kanamono T., Nakano T., Uchimura S., Izumihara T., Yamazaki A., Karyekar C., Takeuchi T.

Modern Rheumatology （Modern Rheumatology） 24 （ 6 ） 885 - 891 2014年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

© 2014 Japan College of Rheumatology. Objective. To evaluate efficacy and safety of subcutaneous (SC) and intravenous (IV) abatacept and background methotrexate (MTX) in Japanese patients with rheumatoid arthritis (RA) and inadequate response to MTX (MTX-IR). Methods. Double-dummy, double-blind study (NCT01001832); 118 adults with ≥ 10 swollen joints, ≥ 12 tender joints and C-reactive protein (CRP) ≥ 0.8 mg/dL randomized 1:1 to SC abatacept (125 mg weekly) with IV loading (~ 10 mg/kg on Day 1), or IV abatacept (~ 10 mg/kg monthly) for 169 days, both also receiving MTX (6-8 mg/week). Primary endpoint was Day 169 American College of Rheumatology (ACR)20 response; other efficacy endpoints, safety and immunogenicity were assessed. Results. Similar proportions of patients achieved ACR20 responses at Day 169 with SC (91.5% [95% CI 81.3, 97.2]) and IV abatacept (83.1% [71.0, 91.6]). ACR50/70 responses, adjusted mean changes from baseline in Health Assessment Questionnaire-Disability Index scores and remission rates (28-joint Disease Activity Score [CRP] < 2.6) were also comparable between groups. Serious adverse event frequencies (5.1% vs. 3.4%) were similar with both formulations. One patient per group tested seropositive for immunogenicity. Weekly SC abatacept dosing achieved mean serum concentrations > 10 μ g/mL (minimum therapeutic target). Conclusions. SC abatacept demonstrated comparable efficacy and safety to IV abatacept, with low immunogenicity rates, in MTX-IR Japanese patients with RA.

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111th Scientific Meeting of the Japanese Society of Internal Medicine: Educational Lecture: 14. Treat to target strategy in rheumatoid arthritis

Takeuchi T., Kaneko Y.

Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine （Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine） 103 （ 9 ） 2321 - 2327 2014年09月

研究論文（学術雑誌）, 査読有り, ISSN 00215384

Early response to certolizumab pegol predicts long-term outcomes in patients with active rheumatoid arthritis: Results from the Japanese studies

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

Modern Rheumatology （Modern Rheumatology） 25 （ 1 ） 11 - 20 2014年05月

研究論文（学術雑誌）, 査読有り, ISSN 14397595

© 2014 Japan College of Rheumatology. Objectives. A post-hoc analysis was performed to determine the relationship between the timing and magnitude of DAS28(ESR) response and long term outcomes in Japanese patients after 1 year of CZP treatment. Methods. Our analysis included 82 J-RAPID trial patients treated with CZP 200 mg and methotrexate, and 116 HIKARI trial patients treated with CZP 200 mg alone or with disease-modifying agents other than methotrexate. Remission rates and changes in mTSS at year 1 were compared to the DAS28(ESR) response at week 12 of CZP treatment. Results. After 1 year of treatment, remission was achieved in 41.3% of the J-RAPID and 34.9% of the HIKARI patients with a week 12 DAS28(ESR) response of ≥ 1.2. In comparison, patients with a DAS28(ESR) response of ≥ 1.2 at week 12 only had a ≥ 7% probability of achieving remission and displayed higher change in mTSS after 1-year treatment. Conclusions. The likelihood of remission and extent of radiographic progression after 1 year was associated with the week 12 DAS28(ESR) response. The DAS28(ESR) response at 12 weeks could be benefi cial for identifying patients that are unlikely to respond to prolonged CZP treatment.

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Adalimumab, a human anti-TNF monoclonal antibody, outcome study for the prevention of joint damage in Japanese patients with early rheumatoid arthritis: The HOPEFUL 1 study

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

Annals of the Rheumatic Diseases （Annals of the Rheumatic Diseases） 73 （ 3 ） 536 - 543 2014年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

Objectives To evaluate the efficacy and safety of adalimumab+methotrexate (MTX) in Japanese patients with early rheumatoid arthritis (RA) who had not previously received MTX or biologics. Methods This randomised, double-blind, placebo-controlled, multicentre study evaluated adalimumab 40 mg every other week+MTX 6-8 mg every week versus MTX 6-8 mg every week alone for 26 weeks in patients with RA (≤2-year duration). The primary endpoint was inhibition of radiographic progression (change (Δ) from baseline in modified total Sharp score (mTSS)) at week 26. Results A total of 171 patients received adalimumab+MTX (mean dose, 6.2±0.8 mg/week) and 163 patients received MTX alone (mean dose, 6.6±0.6 mg/week, p<0.001). The mean RA duration was 0.3 years and 315 (94.3%) had high disease activity (DAS28>5.1). Adalimumab+MTX significantly inhibited radiographic progression at week 26 versus MTX alone (ΔmTSS, 1.5±6.1 vs 2.4±3.2, respectively; p<0.001). Significantly more patients in the adalimumab+MTX group (62.0%) did not show radiographic progression (ΔmTSS≤0.5) versus the MTX alone group (35.4%; p<0.001). Patients treated with adalimumab+MTX were significantly more likely to achieve American College of Rheumatology responses and achieve clinical remission, using various definitions, at 26 weeks versus MTX alone. Combination therapy was well tolerated, and no new safety signals were observed. Conclusions Adalimumab in combination with low-dose MTX was well tolerated and efficacious in suppressing radiographic progression and improving clinical outcomes in Japanese patients with early RA and high disease activity.

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Overview of lupus nephritis management guidelines and perspective from Asia

Mok Chi Chiu, Yap Desmond Y H, Navarra Sandra V., Liu Zhi Hong, Zhao Ming Hui, Lu Liangjing, Takeuchi Tsutomu, Avihingsanon Yingyos, Yu Xue Qing, Lapid Elizabeth A., Lugue-Lizardo Lenrore R., Sumethkul Vasant, Shen Nan, Chen Shun Le, Chan Tak Mao

Nephrology 19 （ 1 ） 11 - 20 2014年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1320-5358

Lupus nephritis (LN) is a common and important manifestation of systemic lupus erythematosus (SLE). Evidence suggests higher rates of lupus renal involvement in Asian populations, and maybe more severe nephritis, compared with other racial or ethnic groups. The management of LN has evolved considerably over the past three decades, based on observations from clinical studies that investigated different immunosuppressive agents including corticosteroids, cyclophosphamide, azathioprine, mycophenolic acid, calcineurin inhibitors and novel biologic therapies. This is accompanied by improvements in both the short-term treatment response rate and long-term renal function preservation. Treatment guidelines for LN have recently been issued by rheumatology and nephrology communities in U.S.A. and Europe. In view of the racial difference in disease manifestation and response to therapy, and the substantial disease burden in Asia, a panel of 15 nephrologists and rheumatologists from different Asian regions with extensive experience in lupus nephritis - the Steering Group for the Asian Lupus Nephritis Network (ALNN) - met and discussed the management of lupus nephritis in Asian patients. The group has also reviewed and deliberated on the recently published recommendations from other parts of the world. This manuscript summarizes the discussions by the group and presents consensus views on the clinical management and treatment of adult Asian patients with LN, taking into account both the available evidence and expert opinion in areas where evidence remains to be sought. © 2013 The Authors. Nephrology © 2013 Asian Pacific Society of Nephrology.

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The multicenter study of a new assay for simultaneous detection of multiple anti-aminoacyl-tRNA synthetases in myositis and interstitial pneumonia

竹内勤

PLoS ONE （PLoS ONE） 9 （ 1 ） 89 - 90 2014年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1932-6203

Objective: Autoantibodies to aminoacyl-tRNA synthetases (ARSs) are useful in the diagnosis of idiopathic inflammatory myopathy (IIM) with interstitial pneumonia (IP). We developed an enzyme-linked immunosorbent assay (ELISA) system using a mixture of recombinant ARS antigens and tested its utility in a multicenter study. Methods: We prepared six recombinant ARSs: GST-Jo-1, His-PL-12, His-EJ and GST-KS expressed in Escherichia coli, and His-PL-7 and His-OJ expressed in Hi-5 cells. After confirming their antigenic activity, with the exception of His-OJ, we developed our ELISA system in which the five recombinant ARSs (without His-OJ) were mixed. Efficiency was confirmed using the sera from 526 Japanese patients with connective tissue disease (CTD) (IIM n = 250, systemic lupus erythematosus n = 91, systemic sclerosis n = 70, rheumatoid arthritis n = 75, Sjögren's syndrome n = 27 and other diseases n = 13), 168 with idiopathic interstitial pneumonia (IIP) and 30 healthy controls collected from eight institutes. IIPs were classified into two groups; idiopathic pulmonary fibrosis (IPF) (n = 38) and non-IPF (n = 130). Results were compared with those of RNA immunoprecipitation. Results: Sensitivity and specificity of the ELISA were 97.1% and 99.8%, respectively when compared with the RNA immunoprecipitation assay. Anti-ARS antibodies were detected in 30.8% of IIM, 2.5% of non-myositis CTD, and 10.7% of IIP (5.3% of IPF and 12.3% of non-IPF). Anti-ARS-positive non-IPF patients were younger and more frequently treated with glucocorticoids and/or immunosuppressants than anti-ARS-negative patients. Conclusion: A newly established ELISA detected anti-ARS antibodies as efficiently as RNA immunoprecipitation. This system will enable easier and wider use in the detection of anti-ARS antibodies in patients with IIM and IIP. © 2014 Nakashima et al.

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Effectiveness and safety of tocilizumab: Postmarketing surveillance of 7901 patients with rheumatoid arthritis in Japan

Koike T., Harigai M., Inokuma S., Ishiguro N., Ryu J., Takeuchi T., Takei S., Tanaka Y., Sano Y., Yaguramaki H., Yamanaka H.

Journal of Rheumatology （Journal of Rheumatology） 41 （ 1 ） 15 - 23 2014年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

Objective. An all-patient postmarketing surveillance program was conducted to evaluate the safety and effectiveness of tocilizumab (TCZ) for rheumatoid arthritis (RA) in the real-world clinical setting in Japan. Methods. Patients received 8 mg/kg TCZ every 4 weeks and were observed for 28 weeks. Data were collected on patient characteristics, and drug safety and effectiveness. Results. A total of 7901 patients were enrolled. Percentages of total and serious adverse events (AE) were 43.9% and 9.6%, respectively. The most common serious AE were infections (3.8%). Logistic regression analysis identified the following risk factors for the development of serious infection: age ≥ 65 years, disease duration ≥ 10 years, previous or concurrent respiratory disease, and concomitant corticosteroid dose > 5 mg/day (prednisolone equivalent). The incidence rate of serious infections in patients with ≥ 3 risk factors was 11.2%, compared with 1.2% for patients without risk factors. The Week 28 rates of 28-joint Disease Activity Score-erythrocyte sedimentation rate remission, Boolean remission, and European League Against Rheumatism (EULAR) Good Response were 47.6%, 15.1%, and 59.4%, respectively. Contributing factors for effectiveness were body weight ≥ 40 kg, less advanced RA, no previous biologics, no concomitant corticosteroids or nonsteroidal antiinflammatory drugs, and low disease activity at baseline. From the benefit-risk balance analysis, patients with a high probability of remission and a low probability of developing serious infection were most likely to have less advanced RA and to have not received biologics previously. Conclusion. These data confirm the safety and effectiveness of TCZ in patients with RA in the real-world clinical setting in Japan and identify factors that contribute to the successful use of TCZ for RA. The Journal of Rheumatology Copyright © 2014. All rights reserved.

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Addition of another disease-modifying anti-rheumatic drug to methotrexate reduces the flare rate within 2 years after infliximab discontinuation in patients with rheumatoid arthritis: An open, randomized, controlled trial

Kurasawa T., Nagasawa H., Kishimoto M., Amano K., Takeuchi T., Kameda H.

Modern Rheumatology （Modern Rheumatology） 24 （ 4 ） 561 - 566 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objectives. We examined whether the addition of another conventional disease-modifying anti-rheumatic drugs (DMARDs) to methotrexate (MTX) upon infliximab (IFX) discontinuation in well-controlled rheumatoid arthritis (RA) patients could suppress subsequent disease flare. Methods. RA patients maintaining DAS28-CRP (Disease Activity Score of 28 joints with C-reactive protein) scores < 2.6 for ≥ 6 months with IFX were randomized either to receive addition of bucillamine (BUC) to MTX (BUC + MTX group; n = 24) or not (MTX group; n = 31) upon discontinuing IFX. The primary endpoint was the flare rate within 2 years of IFX discontinuation. Results. Six patients discontinuing MTX during the study were excluded from analyses. Seventeen patients (63.0%) experienced flares in the MTX group, which was significantly reduced in the BUC + MTX group (31.8%; p = 0.045). Further, the flare rates differed significantly between remission and non-remission by a Boolean definition upon IFX discontinuation in the MTX group (40.0% vs. 91.7%, respectively; p = 0.014), but they were comparable in the BUC + MTX group. BUC treatment was interrupted in seven patients due to rash, proteinuria and incompliance. Conclusions. DMARDs combination therapy may be a better treatment strategy than MTX monotherapy for maintaining RA control after successful discontinuation of biological agents. © 2014 The Authors.

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A paradigm shift in rheumatoid arthritis over the past decade

Kaneko Y., Takeuchi T.

Internal Medicine （Internal Medicine） 53 （ 17 ） 1895 - 1903 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0918-2918

© 2014 The Japanese Society of Internal Medicine. Recent advances have improved our understanding of the pathogenesis of rheumatoid arthritis (RA), and the development of new therapeutics, including biological agents, have thus made it possible to strive for remission as a primary goal. Biological agents targeting a specific molecule have powerful functional capabilities, and the introduction of biological therapies has brought about revolutionary progress in RA management, culminating in a paradigm shift. There is clear evidence that a delay in treatment initiation and poor control of disease activity are associated with joint damage progression, so treatment should be started immediately after the diagnosis of RA and adapted according to disease activity as assessed by validated composite measures. In this review, we will summarize the changes in the classification and remission criteria and describe the clinical efficacies of biological agents in RA. We also discuss new promising therapies and propose future perspectives in the rheumatology field.

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

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

Modern Rheumatology 24 （ 1 ） 8 - 16 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

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

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

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

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

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

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

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

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

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

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

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

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

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

Modern Rheumatology 24 （ 1 ） 26 - 32 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

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

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

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

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

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

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

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

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

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

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

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

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

Modern Rheumatology 24 （ 1 ） 17 - 25 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

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

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

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

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

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

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

Modern Rheumatology 24 17 - 25 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

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

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

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

Modern Rheumatology 24 8 - 16 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

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

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

Modern Rheumatology 24 26 - 32 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

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

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

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

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

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

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

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

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

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

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

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

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

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

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

研究論文（学術雑誌）, 共著, 査読有り

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

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

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

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

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

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

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

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

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

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0392-856X

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

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

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

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

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

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

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

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

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

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

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

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

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

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

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

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

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

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

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

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1462-0324

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

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

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

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

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1462-0324

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

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

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

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

研究論文（学術雑誌）, 査読有り, ISSN 09114300

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

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Overview of lupus nephritis management guidelines and perspective from Asia

竹内勤

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

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1756-1841

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

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

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

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

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

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

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

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

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

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

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

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

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

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0770-3198

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

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

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

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

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

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

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

竹内勤

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

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1297-319X

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

竹内勤

Arthritis and Rheumatism 65 S881 - S881 2013年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0004-3591

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

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

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

研究論文（学術雑誌）, 共著, 査読有り

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

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

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

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

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

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

竹内勤

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

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

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

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

Takeuchi T., Suzuki K.

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

研究論文（学術雑誌）, 査読有り, ISSN 14620324

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

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

Kaneko Y., Kondo H., Takeuchi T.

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

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

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

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

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

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

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

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

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

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

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

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

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

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[Anti-cytokine treatment, newly developed].

Hanaoka H., Takeuchi T.

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

研究論文（学術雑誌）, 査読有り, ISSN 00471852

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

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

Kameda H., Takeuchi T.

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

研究論文（学術雑誌）, 査読有り, ISSN 00471852

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

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

竹内勤

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

研究論文（学術雑誌）, ISSN 0003-4967

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

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

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

研究論文（学術雑誌）, 査読有り, ISSN 14397595

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

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

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

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

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

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Safety and efficacy of long-term esomeprazole 20 mg in Japanese patients with a history of peptic ulcer receiving daily non-steroidal anti-inflammatory drugs

竹内勤

BMC Gastroenterology （BMC Gastroenterology） 13 （ 1 ） 189 - 190 2013年03月

研究論文（学術雑誌）, 査読有り, ISSN 1471-230X

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are an effective and common treatment for chronic pain disorders, but long-term use is associated with risk of potentially life-threatening gastrointestinal adverse events (AEs). The proton pump inhibitor esomeprazole has been found to be effective for gastroprotection in NSAID users, but few long-term studies have been conducted in Japan.Methods: This was an open-label, multicentre, single-arm, prospective 1-year study of treatment with esomeprazole (20 mg once daily) in Japanese patients (aged ≥20 years) with endoscopic evidence of previous peptic ulcer and receiving daily oral NSAID therapy (at a stable dose) for a chronic condition. Eligibility was not dictated by type of oral NSAID. The primary objective was to determine long-term safety and tolerability of esomeprazole. Efficacy for prevention of peptic ulcers was also determined (Kaplan-Meier method). All statistical analyses were descriptive.Results: A total of 130 patients (73.1% women, mean age 62.1 years, 43.8% Helicobacter pylori-positive) received treatment with esomeprazole in addition to long-term NSAID therapy (most commonly for rheumatoid arthritis [n=42] and osteoarthritis [n=34]). Loxoprofen, meloxicam and diclofenac were the most commonly used NSAIDs; cyclo-oxygenase (COX)-2 selective agents were used by 16.2% of patients (n=21). Long-term compliance with esomeprazole (capsule counts) was >75% for the majority of patients. Although 16.9% of patients (n=22) experienced AEs judged to be possibly related to treatment with esomeprazole, they were mostly mild and transient. The most commonly reported possibly treatment-related AEs were abnormal hepatic function, headache, increased γ-glutamyltransferase levels and muscle spasms (2 patients each). Overall, 95.9% (95% confidence interval: 92.3, 99.4) of patients remained ulcer free at 1 year.Conclusion: Long-term treatment with esomeprazole (20 mg once daily) is well tolerated and efficacious for preventing ulcer recurrence in Japanese NSAID users with a history of peptic ulcer.Trial registration: ClinicalTrials.gov identifier NCT00595517. © 2013 Sugano et al.; licensee BioMed Central Ltd.

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Validation of different sets of criteria for the diagnosis of Sjögren's syndrome in Japanese patients

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

Modern Rheumatology （Modern Rheumatology） 23 （ 2 ） 219 - 225 2013年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objective: To validate the revised Japanese Ministry of Health criteria for the diagnosis of Sjögren's syndrome (SS) (JPN) (1999), The American-European Consensus Group classification criteria for SS (AECG) (2002), and American College of Rheumatology classification criteria for SS (ACR) (2012). Methods: The study subjects were 694 patients with SS or suspected SS who were followed-up in June 2012 at ten hospitals that form part of the Research Team for Autoimmune Diseases, The Research Program for Intractable Disease by the Ministry of Health, Labor and Welfare (MHLW). All patients had been checked for all four criteria of the JPN (pathology, oral, ocular, anti-SS-A/SS-B antibodies). We studied the clinical diagnosis made by the physician in charge and the satisfaction of the above criteria. Results: Of the 694 patients, 499 patients did not have other connective tissue diseases (CTDs). SS was diagnosed in 476 patients (primary SS in 302, secondary SS in 174), whereas non-SS was diagnosed in 218 patients (without other CTDs in 197, with other CTDs in 21) by the physician in charge. The sensitivities of JPN, AECG, and ACR in the diagnosis of all forms of SS (both primary and secondary SS) were 79.6, 78.6, and 77.5 %, respectively, with respective specificities of 90.4, 90.4, and 83.5 %. The sensitivities of the same systems in the diagnosis of primary SS were 82.1, 83.1, and 79.1 %, respectively, with specificities of 90.9, 90.9, and 84.8 %, respectively. The sensitivities of the same systems in the diagnosis of secondary SS were 75.3, 70.7, and 74.7 %, respectively, with specificities of 85.7, 85.7, and 71.4 %, respectively. Conclusion: The sensitivity of JPN to all forms of SS and secondary SS, the sensitivity of AECG to primary SS, and the specificities of JPN and AECG for all forms of SS, primary SS, and secondary SS were highest in the diagnosis of SS in Japanese patients. These results indicate that the JPN criteria for the diagnosis of SS in Japanese patients are superior to ACR and AECG. © Japan College of Rheumatology 2012.

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A merged presentation of clinical and radiographic data using probability plots in a clinical trial, the JESMR study

Kameda Hideto, Kanbe Katsuaki, Sato Eri, Ueki Yukitaka, Saito Kazuyoshi, Nagaoka Shouhei, Hidaka Toshihiko, Atsumi Tatsuya, Tsukano Michishi, Kasama Tsuyoshi, Shiozawa Shunichi, Tanaka Yoshiya, Yamanaka Hisashi, Takeuchi Tsutomu

Annals of the Rheumatic Diseases 72 （ 2 ） 310 - 312 2013年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

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Efficacy of weekly mizoribine pulse therapy in refractory lupus nephritis

Nishi E., Kameda H., Ogawa H., Nagasawa H., Takei H., Okuyama A., Kurasawa T., Kondo T., Nishimura K., Shirai Y., Sakai R., Ito T., Takeuchi T., Amano K.

Modern Rheumatology （Modern Rheumatology） 23 （ 1 ） 97 - 103 2013年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objective: We investigated the efficacy of a high-dose intermittent dosing treatment method (weekly mizoribine pulse therapy) conceived in the hope of achieving better efficacy by increasing the peak blood levels of mizoribine in patients with refractory lupus nephritis. Methods: Seventeen patients with lupus nephritis who had been resistant to corticosteroid and immunosuppressant therapy received weekly mizoribine pulse therapy. Mizoribine (350 mg) was administered three times at 12 h intervals over 2 consecutive days (700 mg for day 1 and 350 mg for day 2), followed by a washout period from day 3 to day 7. Results: This therapeutic strategy enabled the peak blood levels of mizoribine to be increased to more than 3 μg/mL in most of the patients. Although SLEDAI, anti-ds-DNA antibody titer, CH-50, and serum albumin level did not significantly improve, urinary protein levels decreased, and it was possible to taper the dose of concomitant steroids. Using our definition of clinical response, 10 of the 17 patients were responders and 4 of them were nonresponders. The average peak serum mizoribine concentration of the responders was as high as 3.5 μg/mL. Elevation of serum liver enzymes was seen in 1 patient, and hyperuricemia occurred in 4 cases, but none of these adverse events were serious. Conclusion: Intermittent administration of mizoribine can increase blood levels and may be effective for refractory lupus nephritis. © 2012 Japan College of Rheumatology.

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Interferon α-targeted therapy

Hanaoka H., Takeuchi T.

Japanese Journal of Clinical Immunology （Japanese Journal of Clinical Immunology） 36 （ 4 ） 181 - 188 2013年

研究論文（学術雑誌）, 査読有り, ISSN 09114300

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of autoantibodies to various cellular components. Although many of therapies have shown great efficacy, they often associate with adverse effects. The development of safer therapies for SLE has led to recent emphasis on targeting selected pathways that can be important in the inflammatory process in SLE. The cytokine family of type I interferons (IFNs), and especially the IFNα subtypes, are implicated in pathogenesis of SLE. Genetic polymorphisms of several components of the IFN signaling pathway have been associated with an increased risk of SLE. Therefore, IFNα subtypes have been identified as a potential target for drug development in SLE. There have been developed three agents, IFNα-targeted therapy, Sifalimumab, Rontalizumab and NNC 0152-0000-0001. They are anti-IFNα monoclonal antibodies that bind to and specifically neutralizes most IFNα subtypes, preventing signaling through the type I IFN receptor. The safety and dose-proportional pharmacokinetics of those agents were demonstrated. A larger study is currently ongoing, further safety profile will be evaluated. This review provides an update on the ongoing clinical trials of anti-IFNα therapy and the promise and obstacles in the use of biologics in SLE. © 2013 The Japan Society for Clinical Immunology.

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Discontinuation of adalimumab treatment in rheumatoid arthritis patients after achieving low disease activity

Harigai M., Takeuchi T., Tanaka Y., Matsubara T., Yamanaka H., Miyasaka N.

Modern Rheumatology （Modern Rheumatology） 22 （ 6 ） 814 - 822 2012年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objective We implemented a retrospective study to explore discontinuation of therapy with adalimumab (ADA) without exacerbation in rheumatoid arthritis (RA) patients who had achieved low disease activity (LDA) with the biological agent. Methods We enrolled 46 RA patients who had completed open extension of a double-blind, placebo-controlled trial of ADA monotherapy in Japan and who had LDA (DAS28- CRP <2.7) at the last administration of ADA in the extension trials; this date was defined as week 0 in the present study. Treatment of RA was at the discretion of the attending physician after week 0. The primary endpoint of this study was the percentage of patients who maintained discontinuation of biological agents and LDA for 52 weeks. Results Twenty-four of the enrolled patients continued ADA while the rest discontinued ADA after the administration of the drug at week 0. Fourteen of the 22 patients did not restart biological agents, and 4 (18.2%) of these maintained LDA through week 52. All 4 of these patients had received ADA monotherapy before week 0. Conclusion Some RA patients who have achieved LDA with ADA monotherapy can discontinue the biologic without incurring increased disease activity. A prospective randomized study is required to confirm the results of our study. © Japan College of Rheumatology 2012.

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Pneumocystis jirovecii pneumonia associated with etanercept treatment in patients with rheumatoid arthritis: A retrospective review of 15 cases and analysis of risk factors

Tanaka M., Sakai R., Koike R., Komano Y., Nanki T., Sakai F., Sugiyama H., Matsushima H., Kojima T., Ohta S., Ishibe Y., Sawabe T., Ota Y., Ohishi K., Miyazato H., Nonomura Y., Saito K., Tanaka Y., Nagasawa H., Takeuchi T., Nakajima A., Ohtsubo H., Onishi M., Goto Y., Dobashi H., Miyasaka N., Harigai M.

Modern Rheumatology （Modern Rheumatology） 22 （ 6 ） 849 - 858 2012年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Objectives The association of anti-tumor necrosis factor therapy with opportunistic infections in rheumatoid arthritis (RA) patients has been reported. The goal of this study was to clarify the clinical characteristics and the risk factors of RA patients who developed Pneumocystis jirovecii pneumonia (PCP) during etanercept therapy. Methods We conducted a multicenter, case-control study in which 15 RA patients who developed PCP were compared with 74 RA patients who did not develop PCP during etanercept therapy. Results PCP developed within 26 weeks following the first injection of etanercept in 86.7% of the patients. All PCP patients presented with a rapid and severe clinical course and the overall mortality was 6.7%. Independent risk factors were identified using multivariate analysis and included age ≥65 years [hazard ratio (HR) 3.35, p = 0.037], coexisting lung disease (HR 4.48, p = 0.009), and concomitant methotrexate treatment (HR 4.68, p = 0.005). In patients having a larger number of risk factors, the cumulative probability of developing PCP was significantly higher (p<0.001 for patients with two or more risk factors vs. those with no risk factor, and p = 0.001 for patients with one risk factor vs. those with no risk factor). Conclusion Physicians must consider the possibility of PCP developing during etanercept therapy in RA patients, particularly if one or more risk factors are present. © Japan College of Rheumatology 2012.

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[Rheumatoid arthritis].

Tsukamoto M., Takeuchi T.

Nihon rinsho. Japanese journal of clinical medicine （Nihon rinsho. Japanese journal of clinical medicine） 70 Suppl 8 534 - 538 2012年11月

研究論文（学術雑誌）, 査読有り, ISSN 00471852

[Discussion meeting on rheumatoid arthritis: progress in diagnosis and treatment].

Takeuchi T., Atsumi T., Nagaoka S., Oribe M., Kikuchi J.

Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine （Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine） 101 （ 10 ） 2926 - 2942 2012年10月

研究論文（学術雑誌）, 査読有り, ISSN 00215384

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Clinical characteristics and survival of japanese patients with connective tissue disease and pulmonary arterial hypertension: A single-centre cohort

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

Rheumatology (United Kingdom) （Rheumatology (United Kingdom)） 51 （ 10 ） 1846 - 1854 2012年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1462-0324

Objective. To clarify the characteristics, survival and predictors of mortality in Japanese patients with pulmonary arterial hypertension (PAH) associated with CTD.Methods. This single-centre cohort study enrolled 70 consecutive patients with PAH-CTD who visited a tertiary referral centre in Japan between 1970 and 1990 (n = 30, historical group) and between 2000 and 2009 (n = 40, recent group). Baseline clinical features, haemodynamic parameters and ANA profiles were recorded. The Cox proportional hazards regression model was used to determine independent factors associated with an increased risk of mortality.Results. MCTD and SLE were the major underlying CTDs, comprising 43% and 29% of PAH patients respectively, whereas SSc was less common (19%). Anti-U1RNP antibody was the most prevalent ANA (61%). The cumulative survival rate was significantly better in the recent group in comparison with the historical group (76% vs 26% at 3 years; P < 0.001). When both groups were combined, World Health Organization functional class III or IV at diagnosis was identified as an independent predictor of mortality, whereas modern PAH drug use was associated with a favourable outcome.Conclusion. The major PAH-CTD population in Japan suffers from MCTD or SLE with anti-U1RNP antibody, in contrast to PAH-CTD patients in the USA and Europe. Modern PAH treatment has improved survival rates, but long-term outcomes are still unsatisfactory. Independent predictors of mortality indicate that early diagnosis and the prompt use of PAH drugs should improve survival. © The Author 2012. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.

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Inhibition of plasma IL-6 in addition to maintenance of an efficacious trough level of infliximab associated with clinical remission in patients with rheumatoid arthritis

Takeuchi Tsutomu, Miyasaka Nobuyuki, Tatsuki Yoshihiko, Yano Toshiro, Yoshinari Toru, Abe Tohru, Koike Takao

Annals of the Rheumatic Diseases 71 （ 9 ） 1583 - 1585 2012年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

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JAK3 is involved in BAFF-mediated abnormal production of IL-6 by peripheral monocytes of patients with primary Sjogren's syndrome

竹内勤

Cytokine 59 （ 3 ） 545 - 545 2012年09月

研究論文（学術雑誌）, ISSN 1043-4666

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Investigation of 7-benzylidenenaltrexone derivatives as resistance reverser for chloroquine-resistant Plasmodium chabaudi

Miyata Y., Fujii H., Uenohara Y., Kobayashi S., Takeuchi T., Nagase H.

Bioorganic and Medicinal Chemistry Letters （Bioorganic and Medicinal Chemistry Letters） 22 （ 16 ） 5174 - 5176 2012年08月

研究論文（学術雑誌）, 査読有り, ISSN 0960894X

Derivatives of 7-benzylidenenaltrexone (BNTX), which was recently reported to be an effective chloroquine (CQ)-resistance reverser, were synthesized and evaluated for their CQ-resistance reversing activities. The synthesized derivatives showed CQ-resistance reversing effects. They also reacted with glutathione (GSH) both enzymatically and chemically, and inhibited glutathione reductase activity. 7-Benzyl derivative, which was obtained by reduction of the olefin group in α,β-unsaturated ketone structure of BNTX, also exhibited CQ-resistance reversing effect, but its potency was significantly lower than that of BNTX. These outcomes suggested that the decrease in GSH level could be one of the mechanisms of CQ-resistance reversing effects induced by BNTX derivatives. © 2012 Elsevier B.V. All rights reserved.

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Safety and effectiveness of adalimumab in Japanese rheumatoid arthritis patients: Postmarketing surveillance report of the first 3,000 patients

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

Modern Rheumatology （Modern Rheumatology） 22 （ 4 ） 498 - 508 2012年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

This interim analysis of postmarketing surveillance data for adalimumab-treated rheumatoid arthritis (RA) patients summarizes safety and effectiveness during the first 24 weeks of therapy for the first 3,000 patients treated in Japan (June 2008-December 2009). Patient eligibility for antitumor necrosis factor therapy was based on the Japanese College of Rheumatology treatment guidelines and Japanese labeling. All patients were screened for tuberculosis. Approximately 50% of the population was biologic näve, 66% received concomitant methotrexate (MTX), and 72% received concomitant glucocorticoids. The overall incidence rate of adverse events was 31% (5.5% serious) and that of adverse drug reactions (ADRs) was 27% (4.1% serious). Incidence rates of ADRs and serious ADRs were similar regardless of prior biologic therapy or concomitant MTX use but were significantly higher in patients receiving glucocorticoids compared with those not receiving glucocorticoids. Bacterial/bronchial pneumonia occurred in 1.2% of patients; Interstitial pneumonia, 0.6%; Pneumocystis jirovecii pneumonia, 0.3%; tuberculosis, 0.13%; and administration-site reactions, 6.1%. Mean 28-joint Disease Activity Scores decreased significantly after 24 weeks from 5.29 to 3.91. All subgroups showed significant improvement, particularly the biologic-naïve patients receiving concomitant MTX. No new safety concerns were identified. ADR Incidence rates were similar to those of other biologic agents approved for RA. © Japan College of Rheumatology 2011.

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Randomised clinical trial: Esomeprazole for the prevention of nonsteroidal anti-inflammatory drug-related peptic ulcers in Japanese patients

竹内勤

Alimentary Pharmacology and Therapeutics （Alimentary Pharmacology and Therapeutics） 36 （ 2 ） 115 - 125 2012年07月

研究論文（学術雑誌）, 査読有り, ISSN 0269-2813

Summary Background The use of proton pump inhibitors for prevention of nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal adverse events is well documented. However, data regarding the efficacy and safety of this approach in Japan are scarce. Aim To evaluate the efficacy and tolerability of esomeprazole in preventing NSAID-induced peptic ulcers in Japanese at-risk patients. Methods Male and female Japanese adult patients (aged ≥20 years) with endoscopically confirmed history of peptic ulcers who required long-term oral NSAID therapy for a chronic inflammatory condition were randomised to 24 weeks' treatment with esomeprazole 20 mg once daily or matching placebo. The primary end point was the Kaplan-Meier estimated proportion of ulcer-free patients. Results Overall, 343 patients were randomised to treatment (esomeprazole, n = 175; placebo, n = 168). The Kaplan-Meier estimated ulcer-free rate over the 24-week treatment period was significantly higher (log-rank P < 0.001) in esomeprazole-treated patients (96.0%; 95% CI 92.8, 99.1) than in placebo recipients (64.4%; 95% CI 56.8, 71.9). Esomeprazole was effective at preventing peptic ulcers in both Helicobacter pylori-positive and -negative patients (96.3% vs. 95.5% of patients ulcer-free, respectively); however, in the placebo group, the proportion of ulcer-free patients at 24 weeks was markedly lower among H. pylori-positive than -negative patients (59.7% vs. 69.9%). The NSAID type did not seem to affect the estimated ulcer-free rate with esomeprazole. Treatment with esomeprazole was well tolerated. Conclusion Esomeprazole 20 mg once daily is effective and safe in preventing ulcer recurrence in Japanese patients with a definite history of peptic ulcers who were taking an NSAID (identifier: NCT00542789). © 2012 Blackwell Publishing Ltd.

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Safety and effectiveness responses to etanercept for rheumatoid arthritis in Japan: A sub-analysis of a post-marketing surveillance study focusing on the duration of rheumatoid arthritis

Koike T., Harigai M., Inokuma S., Ishiguro N., Ryu J., Takeuchi T., Tanaka Y., Yamanaka H., Fujii K., Yoshinaga T., Freundlich B., Suzukawa M.

Rheumatology International （Rheumatology International） 32 （ 6 ） 1511 - 1519 2012年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0172-8172

The aim is to investigate the relationship of duration of rheumatoid arthritis (RA) with safety and effectiveness of etanercept (ETN) in Japan. Post-marketing surveillance data for 7,099 patients treated with ETN were analyzed. Baseline characteristics, treatment effectiveness, incidence of adverse events (AEs), and serious AEs (SAEs) in relation to duration of RA were studied. At baseline, patients with RA for longer duration were older, weighed less, had more comorbidities, allergies, and corticosteroid use, but smoked less and had less morning stiffness. By 2-5 years with RA, more than half of the patients had advanced to Steinbrocker radiographic stage III or IV. Methotrexate (MTX) was the most commonly used pretreatment disease-modifying antirheumatic drug; however, concomitant MTX use and its dose were lower among patients with longer duration of RA. Remission rates (26.6%) were greatest among patients having RA for <2 years. Less AEs and SAEs were observed among patients with shorter duration of RA. These results suggest that RA treatment in Japan in the era pre-biologics may not have been adequate to control disease activity and prevent joint destruction. Patients with shorter duration of RA may have better physical status which allows the opportunity to treat more intensively putting a higher percentage of patients in remission and possibly decreasing exposure to SAEs. © Springer-Verlag 2011.

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A MULTI-CENTER, DOUBLE-DUMMY, DOUBLE-BLIND STUDY OF SUBCUTANEOUS (SC) ABATACEPT (ABA) COMPARED WITH INTRAVENEOUS (IV) ABA IN JAPANESE RHEUMATOID ARTHRITIS PATIENTS WITH INADEQUATE RESPONSE TO METHOTREXATE

竹内勤

Annals of the Rheumatic Diseases 71 197 - 197 2012年06月

研究論文（学術雑誌）, ISSN 0003-4967

Safety and effectiveness of switching from infliximab to etanercept in patients with rheumatoid arthritis: Results from a large Japanese postmarketing surveillance study

竹内勤

Rheumatology International （Rheumatology International） 32 （ 6 ） 1617 - 1624 2012年06月

研究論文（学術雑誌）, 査読有り, ISSN 0172-8172

Finding an effective treatment strategy for rheumatoid arthritis (RA) patients who have not benefited from previous tumor necrosis factor-α antagonist treatment is important for minimizing RA disease activity and improving patient outcomes. The aim of this study was to compare the safety and effectiveness of etanercept in patients with and without infliximab (IFX) treatment experience. Patients (n = 7,099) from a large postmarketing observational study of etanercept use in Japan were divided into 2 cohorts based on previous IFX use (pre-IFX and non-IFX). Baseline characteristics were assessed in each cohort. Adverse events (AEs) and European League Against Rheumatism (EULAR) responses were monitored every 4 weeks for 24 weeks. At baseline, pre-IFX patients were younger and had fewer comorbidities and a shorter RA duration than non-IFX patients. During the study, pre-IFX patients received concomitant methotrexate more often than non-IFX patients. The incidence of AEs and serious AEs were significantly lower in pre-IFX patients, as was the percentage of patients who discontinued treatment. Both cohorts had significant improvement (P<0.001) in EULAR responses at the end of the treatment period. This study demonstrated that etanercept was effective and well tolerated in active RA patients with and without prior IFX treatment. © Springer-Verlag 2011.

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Effectiveness and safety of adalimumab in Japanese patients with rheumatoid arthritis: Retrospective analyses of data collectedduring the first year of adalimumab treatment in routine clinical practice (HARMONY study)

Takeuchi T., Tanaka Y., Kaneko Y., Tanaka E., Hirata S., Kurasawa T., Kubo S., Saito K., Shidara K., Kimura N., Nagasawa H., Kameda H., Amano K., Yamanaka H.

Modern Rheumatology （Modern Rheumatology） 22 （ 3 ） 327 - 338 2012年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

We retrospectively investigated the ability of adalimumab (ADA) to reduce disease activity, improve physical function, and retard the progression of structural damage in 167 patients with rheumatoid arthritis. Clinicaland functional outcomes were compared between patients with or without prior biologic treatment and those with or without concomitant methotrexate (MTX) treatment. At week 52, 38.3% achieved clinical remission: 42.4 and 28.6% of patients achieved remission in those without and with previous biologics, respectively, while 42.7 and 12.5% of patients achieved remission in those with and without concomitant MTX, respectively. ADA treatment significantly reduced the rate of radiographic progression from 27.1 ± 46.0 (median 13.6; 25th-75th percentiles 8.3 to 28.9) at baseline to 0.8 ± 5.0 (median 0.0; 25th-75th percentiles -0.9 to 2.0) at week 52 (P\0.0001). Radiographic progression was absent in 59.8% of patients. Sixty adverse events (34.21/100 patient-years) were reported, 16 of which were serious (9.12/100 patient-years). ADA therapy is highly effective for reducing disease activity, improving physical function, and limiting radiographic progression. It is generally safe and well tolerated by Japanese RA patients in routine clinical practice. © Japan College of Rheumatology 2011.

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Golimumab in combination with methotrexate in Japanese patients with active rheumatoid arthritis: Results of the GO-FORTH study

Tanaka Y., Harigai M., Takeuchi T., Yamanaka H., Ishiguro N., Yamamoto K., Miyasaka N., Koike T., Kanazawa M., Oba T., Yoshinari T., Baker D.

Annals of the Rheumatic Diseases （Annals of the Rheumatic Diseases） 71 （ 6 ） 817 - 824 2012年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

Objective: To assess the efficacy and safety of golimumab + methotrexate (MTX) in Japanese patients with active rheumatoid arthritis (RA). Methods: 269 Japanese patients with active RA despite treatment with MTX were randomised (1:1:1) to placebo + MTX (Group 1), golimumab 50 mg + MTX (Group 2) or golimumab 100 mg + MTX (Group 3). Subcutaneous golimumab/placebo was injected every 4 weeks; stable doses of oral MTX (6-8 mg/week) were continued. Patients were allowed to enter early escape (Group 1 added golimumab 50 mg, Group 2 increased golimumab to 100 mg, Group 3 continued golimumab 100 mg) based on swollen/tender joint counts at week 14. The primary study endpoint was achievement of at least 20% improvement in the American College of Rheumatology (ACR20) response criteria at week 14. To control for multiplicity of testing, treatment group comparisons were first made between combined Groups 2 and 3 versus Group 1, followed by comparisons of Group 2 and Group 3 versus Group 1. Results: The proportion of patients with an ACR20 response at week 14 was significantly higher in combined Groups 2 and 3 (73.4%, 127/173) and in each of Group 2 (72.1%, 62/86) and Group 3 (74.7%, 65/87) compared with Group 1 (27.3%, 24/88; p<0.0001 for all comparisons). Golimumab + MTX also elicited a significantly better response than placebo + MTX in other efficacy parameters, including disease activity score (DAS28) response/remission and radiographic assessments. During the 16-week fixed treatment regimen study period, 72.7%, 75.6% and 78.2% of patients had adverse events and 1.1%, 1.2% and 2.3% had serious adverse events in Groups 1, 2 and 3, respectively. Conclusion: In Japanese patients with active RA despite MTX therapy, golimumab + MTX was significantly more effective than MTX monotherapy in reducing RA signs/symptoms and limiting radiographic progression with no unexpected safety concerns.

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Clinical significance of cartilage biomarkers for monitoring structural joint damage in rheumatoid arthritis patients treated with anti-TNF therapy

Niki Y., Takeuchi T., Nakayama M., Nagasawa H., Kurasawa T., Yamada H., Toyama Y., Miyamoto T.

PLoS ONE （PLoS ONE） 7 （ 5 ） 2012年05月

研究論文（学術雑誌）, 共著, 査読有り

Purpose: With the current use of biologics in rheumatoid arthritis (RA), there is a need to monitor ongoing structural joint damage due to the dissociation of articular cartilage damage from disease activity of RA. This study longitudinally analyzed levels of serum cartilage biomarkers during 54 weeks of infliximab therapy, to evaluate the feasibility of biomarkers for monitoring structural joint damage. Methods: Subjects comprised 33 patients with early RA and 33 patients with established RA. All patients received 3 mg/kg of infliximab and methotrexate for 54 weeks. Levels of the following serum cartilage markers were measured at baseline and at weeks 14, 22, and 54: hyaluronan (HA); cartilage oligometric matrix protein (COMP); type II collagen (CII)-related neoepitope (C2C); type II procollagen carboxy-propeptide (CPII); and keratin sulfate (KS). Time courses for each biomarker were assessed, and relationships between these biomarkers and clinical or radiographic parameters generally used for RA were investigated. Results: Levels of CRP, MMP-3, DAS28-CRP, and annual progression of TSS were improved to similar degrees in both groups at week 54. HA and C2C/CPII were significantly decreased compared to baseline in the early RA group (p&0.001), whereas HA and COMP, but not C2C/CPII, were decreased in the established RA group. Strikingly, serum C2C/CPII levels were universally improved in early RA, regardless of EULAR response grade. Both ΔHA and ΔC2C/CPII from baseline to week 54 correlated significantly with not only ΔCRP, but also ΔDAS28 in early RA. Interestingly, when partial correlation coefficients were calculated by standardizing CRP levels, the significant correlation of ΔHA to ΔDAS28 disappeared, whereas correlations of ΔC2C/CPII to ΔDAS28, ΔJNS, and ΔHAQ remained significant. These results suggest a role of ΔC2C/CPII as a marker of ongoing structural joint damage with the least association with CRP, and that irreversible cartilage damage in established RA limits restoration of the C2C/CPII level, even with tight control of joint inflammation. Conclusion: The temporal course of C2C/CPII level during anti-TNF therapy indicates that CII turnover shifts toward CII synthesis in early RA, but not in established RA, potentially due to irreversible cartilage damage. ΔC2C/CPII appears to offer a useful marker reflecting ongoing structural joint damage, dissociated from inflammatory indices such as CRP and MMP-3. © 2012 Niki et al.

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Lansoprazole for secondary prevention of gastric or duodenal ulcers associated with long-term non-steroidal anti-inflammatory drug (NSAID) therapy: Results of a prospective, multicenter, double-blind, randomized, double-dummy, active-controlled trial

竹内勤

Journal of Gastroenterology （Journal of Gastroenterology） 47 （ 5 ） 540 - 552 2012年05月

研究論文（学術雑誌）, 査読有り, ISSN 0944-1174

Background Low-dose lansoprazole has not been intensively evaluated for its efficacy in the prevention of recurrent gastric or duodenal ulcers in patients receiving long-term non-steroidal anti-inflammatory drug (NSAID) therapy for pain relief in such diseases as rheumatoid arthritis, osteoarthritis, and low back pain. Methods This multi-center, prospective, double-blind, randomized, active-controlled study involving 99 sites in Japan was designed to compare the efficacy of lansoprazole (15 mg daily) with gefarnate (50 mg twice daily). Patients with a history of gastric or duodenal ulcers who required long-term NSAID therapy were randomized to receive lansoprazole 15 mg daily (n = 185) or gefarnate 50 mg twice daily (n = 181) and followed up for 12 months or longer prospectively. Results The cumulative incidence of gastric or duodenal ulcer at days 91, 181, and 361 from the start of the study was calculated by the Kaplan-Meier method as 3.3, 5.9, and 12.7%, respectively, in the lansoprazole group versus 18.7, 28.5, and 36.9%, respectively, in the gefarnate group. The risk for ulcer development was significantly (log-rank test, P<0.0001) lower in the lansoprazole group than in the gefarnate group, with the hazard ratio being 0.2510 (95% CI 0.1400-0.4499). A long-term follow-up study showed an acceptable safety profile for low-dose lansoprazole therapy, with diarrhea as the most frequent adverse event. Conclusion Lansoprazole was superior to gefarnate in reducing the risk of gastric or duodenal ulcer recurrence in patients with a definite history of gastric or duodenal ulcers who required long-term NSAID therapy. © 2012 Springer.

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CD3 ζ defects in systemic lupus erythematosus.

Takeuchi Tsutomu, Suzuki Katsuya, Kondo Tsuneo, Yoshimoto Keiko, Tsuzaka Kensei

Annals of the Rheumatic Diseases 71 Suppl 2 2012年04月

研究論文（学術雑誌）, 共著, 査読有り

The prototype autoimmune disease, systemic lupus erythematosus (SLE), has been known to be associated with deficiency of ζ chain, a component of the T-cell receptor-CD3 complex. Comprehensive analysis has shown that expression of the CD3 ζ chain is attenuated or absent in over half of SLE patients. Furthermore, aberrant transcripts of the CD3 ζ chain, including spliced variants lacking exon 7 or having a short 3'-untranslated region, have been detected in SLE T cells. Although attenuated expression of the CD3 ζ chain is also observed in cancer patients, infections and other autoimmune diseases, sustained attenuation of the CD3 ζ expression accompanied with aberrant transcripts are only observed in SLE. In this study, the authors review the unique features of CD3 ζ defects observed in SLE and discuss the molecular basis of the defects by recent findings in animal models, single-nucleotide polymorphisms and genome-wide association studies.

Clinicopathological analyses in patients with other iatrogenic immunodeficiency-associated lymphoproliferative diseases and rheumatoid arthritis

竹内勤

Leukemia and Lymphoma （Leukemia and Lymphoma） 53 （ 4 ） 616 - 623 2012年04月

研究論文（学術雑誌）, 査読有り, ISSN 1042-8194

Despite numerous attempts to uncover the mechanism of other iatrogenic immunodeficiency-associated lymphoproliferative diseases (OIIA-LPDs), this mechanism remains poorly understood, especially in rheumatoid arthritis (RA) patients. We analyzed the data on 23 patients with LPDs and RA. Patients were categorized into three groups according to whether they had methotrexate (MTX); MTX-regressive LPDs, MTX-persistent LPDs or other drugs-mediated LPDs. The LPDs seen in OIIA-LPDs-RA might have a unique behavior to think about several rare phenotypes. The overall survival of all patients was 74% at 5 years, and those of the three groups were 100%, 64% and 60%, respectively. Among the 6 patients who died, 4 had LPDs that were detected late, and thus adequate treatment was not given. In addition, several patients with diffuse large B cell lymphoma with a complex karyotype achieved complete remission (CR). Only one among the 17 patients who achieved CR relapsed. OIIA-LPDs-RA appeared to have a better prognosis than other more common types of lymphomas. Regarding RA treatment, various anti-RA drugs were given to the patients after developing LPDs, including MTX, but no recurrent patients were documented. © 2012 Informa UK, Ltd.

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Critical role of CD4+CD25+ regulatory T cells in preventing murine autoantibody-mediated thrombocytopenia

竹内勤

Experimental Hematology （Experimental Hematology） 40 （ 4 ） 279 - 289 2012年04月

研究論文（学術雑誌）, 査読有り, ISSN 0301-472X

Autoimmune response suppression by regulatory T cells (Tregs) helps to maintain peripheral immune tolerance, and defects in this mechanism are thought to play a role in the pathogenesis of various autoimmune diseases. In patients with immune thrombocytopenia, naturally occurring CD4+CD25+ Tregs are both functionally impaired and reduced in number. This study was undertaken to investigate Tregs' role in preventing immune thrombocytopenia in mice. Treg-deficient mice were prepared by inoculation of Treg-depleted CD4+CD25- T cells isolated from BALB/c mice into syngeneic nude mice intravenously. Platelet count, proportion of reticulated platelets, platelet-associated IgG, platelet-associated anti-platelet antibodies, and IgG anti-platelet antibody production in splenocyte cultures were examined by flow cytometry. Of 69 Treg-deficient mice, 25 (36%) spontaneously developed thrombocytopenia that lasted at least 5 weeks. The platelet-associated IgG level and proportion of reticulated platelets were elevated in the thrombocytopenic mice. Platelet eluates and splenocyte culture supernatants prepared from thrombocytopenic mice, but not from nonthrombocytopenic mice, contained IgG antibodies capable of binding to intact platelets. Simultaneous transfer of Tregs completely prevented the onset of thrombocytopenia, but Treg transfer after the onset of thrombocytopenia had no apparent effect. Treatment with IgG anti-cytotoxic T lymphocyte-associated antigen 4 antibody canceled this Treg-governed suppressive effect. In summary, these results indicate that Tregs play a critical role in preventing murine autoantibody-mediated thrombocytopenia by engaging cytotoxic T lymphocyte-associated antigen 4. © 2012 ISEH - Society for Hematology and Stem Cells.

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CD3 ξ defects in systemic lupus erythematosus

Takeuchi T., Suzuki K., Kondo T., Yoshimoto K., Tsuzaka K.

Annals of the Rheumatic Diseases （Annals of the Rheumatic Diseases） 71 （ SUPPL. 2 ） i78 - i81 2012年04月

研究論文（学術雑誌）, 査読有り, ISSN 0003-4967

The prototype autoimmune disease, systemic lupus erythematosus (SLE), has been known to be associated with deficiency of ξ chain, a component of the T-cell receptor-CD3 complex. Comprehensive analysis has shown that expression of the CD3 ξ chain is attenuated or absent in over half of SLE patients. Furthermore, aberrant transcripts of the CD3 ξ chain, including spliced variants lacking exon 7 or having a short 3′-untranslated region, have been detected in SLE T cells. Although attenuated expression of the CD3 ξ chain is also observed in cancer patients, infections and other autoimmune diseases, sustained attenuation of the CD3 ξ expression accompanied with aberrant transcripts are only observed in SLE. In this study, the authors review the unique features of CD3 ξ defects observed in SLE and discuss the molecular basis of the defects by recent findings in animal models, single-nucleotide polymorphisms and genome-wide association studies.

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Structural damages disturb functional improvement in patients with rheumatoid arthritis treated with etanercept

Tanaka Y., Yamanaka H., Saito K., Iwata S., Miyagawa I., Seto Y., Momohara S., Nagasawa H., Kameda H., Kaneko Y., Izumi K., Amano K., Takeuchi T.

Modern Rheumatology （Modern Rheumatology） 22 （ 2 ） 186 - 194 2012年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Tumor necrosis factor (TNF) inhibitors have produced improvements in clinical, radiographic, and functional outcomes in rheumatoid arthritis (RA) patients. However, it remains unclear whether factors affecting physical functions remain following TNF therapy. The objective of our study was to assess factors affecting improvement of physical functions and to shed light on relations to disease activity and structural changes in patients with RA treated with etanercept. The study enrolled 208 patients, all of whose composite measures regarding clinical, radiographic, and functional estimation both at 0 and 52 weeks after etanercept therapy were completed. Mean disease duration of 208 patients was 9.6 years, mean Disease Activity Score for 28 joints (DAS28) was 5.4, and mean van der Heijde modified total Sharp score (mTSS) was 94.6. Mean Health Assessment Questionnaire Disability Index (HAQ-DI) improved from 1.4 at 0 weeks to 1.0 at 52 weeks after etanercept therapy, a 31% reduction, which was much less than changes in DAS28 and mTSS. By multivariate analysis, HAQ-DI and mTSS at baseline were significantly correlated HAQ remission. Median HAQ-DI improved in 100 versus 20% of the HAQ-DI ≤0.6 versus ≥2.0 groups, respectively. The mTSS cutoff point at baseline to obtain HAQ remission was 55.5. During etanercept treatment in the mTSS <55.5 versus >55.5 groups, median HAQ-DI improved in 70 versus 39%; remission was achieved in 59 versus 33%; and there was no improvement in 14 versus 30%, respectively. HAQ-DI improvement was significantly correlated with that of DAS28 but not of mTSS. In conclusion, higher HAQ and mTSS at baseline inhibits HAQ-DI improvement within 1 year of etanercept treatment, and the cutoff point necessary for mTSS to improve physical functions in patients with RA was 55.5. © Japan College of Rheumatology 2011.

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What is the future of CCR5 antagonists in rheumatoid arthritis?

Takeuchi Tsutomu, Kameda Hideto

Arthritis Research and Therapy 14 （ 2 ） R11 2012年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1478-6354

Fleishaker and colleagues reported on a double-blind placebo controlled clinical trial of a C-C chemokine-receptor type 5 (CCR5) antagonist, maraviroc, in rheumatoid arthritis (RA) patients with inadequate response to methotrexate, showing that it was ineffective. Two additional CCR5 antagonists, SCH351125 and AZD5672, also failed to demonstrate clinical efficacy. In addition, CCR5-blocking antibodies could not inhibit synovial fluid-induced monocyte chemotaxis. Thus, CCR5 appears not to be a desirable target in RA treatment. Given the multiple functions of CCR5, redundancies in the chemokine system, and patient selection in the trial, we overview the recent understanding for chemokine receptor blockade in the treatment of RA. © 2012 BioMed Central Ltd.

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[The 39th scientific meeting: perspectives of internal medicine; the cutting edge of treatment of medical disorders encountered in clinical practice; 9. Progress in RA management].

Takeuchi T.

Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine （Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine） 101 （ 3 ） 647 - 653 2012年03月

研究論文（学術雑誌）, 査読有り, ISSN 00215384

Successful treatment of adult-onset Still's disease with tocilizumab monotherapy: Two case reports and literature review

Sakai R., Nagasawa H., Nishi E., Okuyama A., Takei H., Kurasawa T., Kondo T., Nishimura K., Shirai Y., Ito T., Kameda H., Takeuchi T., Amano K.

Clinical Rheumatology （Clinical Rheumatology） 31 （ 3 ） 569 - 574 2012年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0770-3198

Adult-onset Still's disease (AOSD) is a systemic inflammatory disease of unknown etiology. Recently, it has been reported that quite a few cases of refractory AOSD were successfully treated with tocilizumab (TCZ) and corticosteroids were withdrawn in some of these patients. We report two AOSD patients who were treated successfully with TCZ monotherapy; thus, avoiding corticosteroid treatment. Because both of the patients refused to take corticosteroids, we planned to treat them with 8 mg/kg of TCZ monotherapy at weeks 0, 2, 6 and subsequently every 4 weeks. The efficacy of TCZ was assessed by patients' clinical symptoms such as fever, arthralgia, skin eruptions, and laboratory markers such as serum levels of CRP, ferritin, and IL-6. We also reviewed 14 previous case reports including 30 cases who had been treated with TCZ for AOSD. Our patients responded rapidly and have been maintained in clinical remission without corticosteroid treatment. In the literature review, concomitant corticosteroid treatment described in 13 cases was successfully tapered in 7 and discontinued in 6 cases. TCZ monotherapy can be a candidate for the first-line therapy for some AOSD patients. © 2011 Clinical Rheumatology.

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[Clinical significance of serum cartilage biomarkers in the treatment of rheumatoid arthritis with biological therapy].

Niki Y., Takeuchi T.

Clinical calcium （Clinical calcium） 22 （ 2 ） 205 - 212 2012年02月

研究論文（学術雑誌）, 査読有り, ISSN 09175857

With the current use of biologics in RA, numerous patients can achieve clinical remission, however structural joint damage occurs in substantial numbers of the patients. The present study assessed cartilage damage during 54-week anti-TNF therapy, using serum cartilage markers, and potential advantages of these markers were evaluated. Levels of serum hyaluronan decreased with decreasing levels of CRP in both early and established RA, whereas indicator of type II collagen synthesis/degradation, C2C/CP II decreased only in early RA group. Levels of COMP and keratin sulfate significantly decreased and increased compared to baseline, respectively, by week 54 in established RA. Strikingly, C2C/CP II levels were universally improved in early RA, regardless of CRP levels or EULAR response grade. In contrast, C2C/CP II levels universally worsened in established RA, even though patients achieved good response. As a role of surrogate marker reflecting therapeutic efficacy of biological therapy, C2C/CP II appears particularly useful for determining the degree of ongoing structural joint deterioration, which is dissociated from clinical assessment of disease activity in RA.

Postmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan

Koike Takao, Harigai Masayoshi, Inokuma Shigeko, Ishiguro Naoki, Ryu Junnosuke, Takeuchi Tsutomu, Takei Syuji, Tanaka Yoshiya, Ito Kyoko, Yamanaka Hisashi

Annals of the Rheumatic Diseases 70 （ 12 ） 2148 - 2151 2011年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

Objective: An interim analysis of an all-patient postmarketing surveillance programme in Japan to investigate the safety of tocilizumab for the treatment of rheumatoid arthritis (RA) in the real world. Methods: This analysis included 3881 patients. Patients received 8 mg/kg of tocilizumab every 4 weeks, and were observed for 28 weeks. Data on baseline characteristics and adverse events (AE) were collected. Results: Total and serious AE were reported as 167 and 27 events/100 patient-years, respectively. The most frequent AE and serious AE were infections. Logistic regression analysis identified the following risk factors for the development of serious infection: concurrent or medical history of respiratory disorders; prednisolone dose at baseline ≥5 mg/day; and age ≥65 years. Twenty-five patients died, and the standardised mortality ratio, with the Japanese general population in 2008 as reference, was 1.66, similar to the results from the Japanese cohort study for RA patients. Conclusions: Tocilizumab is acceptably safe in the real clinical setting. Tocilizumab needs to be used with consideration of the benefit-risk balance to avoid serious infections in elderly patients and those on high doses of corticosteroids or with a concurrent or medical history of respiratory disorders.

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Treating rheumatoid arthritis to target

Haraoui Boulos, Smolen Josef S., Aletaha Daniel, Breedveld Ferdinand C., Burmester Gerd, Codreanu Catalin, Da Silva José Pereira, De Wit Maarten, Dougados Maxime, Durez Patrick, Emery Paul, Fonseca João Eurico, Gibofsky Allan, Gomez-Reino Juan, Graninger Winfried, Hamuryudan Vedat, Peña Maria José Jannaut, Kalden Joachim, Kvien Tore K., Laurindo Ieda, Martin-Mola Emilio, Montecucco Carlomaurizio, Moreno Pedro Santos, Pavelka Karel, Poor Gyula, Cardiel Mario H., Stanislawska-Biernat Ewa, Takeuchi Tsutomu, Van Der Heijde Désirée, Awadhi Adel Al, AlShehhi Waleed Yousef, Babic-Naglic Durda, Michel Beat A., Galarza-Maldonado Claudio, Hammoudeh Mohammed, Harrison Michael, Kolarov Zlatimir, Lee Soo Kon, Nash Peter, Otsa Kati, Sokka Tuulikki, Tate Guillermo A., Tomsic Matija, Uthman Imad, Venalis Algirdas, De Morales Sol Villegas

Annals of the Rheumatic Diseases 70 （ 11 ） 1999 - 2002 2011年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

Aim: To measure the level of agreement and application of 10 international recommendations for treating rheumatoid arthritis (RA) to a target of remission/low disease activity. Methods: A 10-point Likert scale (1=fully disagree, 10=fully agree) measured the level of agreement with each of 10 recommendations. A 4-point Likert scale (never, not very often, very often, always) assessed the degree to which each recommendation was being applied in current daily practice. If respondents answered 'never' or 'not very often', they were asked whether they would change their practice according to the particular recommendation. Results: A total of 1901 physicians representing 34 countries participated. Both agreement with and application of recommendations was high. With regard to application of recommendations in daily practice, the majority of responses were 'always' and 'very often'. A significant percentage of participants who were currently not applying these recommendations in clinical practice were willing to change their practice according to the recommendations. Conclusion: The results of this survey demonstrated great support of 'Treating RA to Target' recommendations among the international rheumatology community. Additional efforts may be needed to encourage application of the recommendations among certain clinicians who are resistant to changing their practice.

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T Helper Type 1-Bias in a Regulatory T Cell-Deficient Mouse Model for Immune Thrombocytopenia

竹内勤

BLOOD 118 （ 21 ） 243 - 244 2011年11月

研究論文（学術雑誌）, ISSN 0006-4971

Regulatory mechanisms for the production of BAFF and IL-6 are impaired in monocytes of patients of primary Sjogren's syndrome

Yoshimoto Keiko, Tanaka Maiko, Kojima Masako, Setoyama Yumiko, Kameda Hideto, Suzuki Katsuya, Tsuzaka Kensei, Ogawa Yoko, Tsubota Kazuo, Abe Tohru, Takeuchi Tsutomu

Arthritis Research & Therapy 13 R170 2011年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1478-6354

Introduction: In this study, we investigated possible aberrations of monocytes from patients with primary Sjogren's syndrome (pSS). We focused on BAFF (B cell activating factor of the TNF family) and IL-6, because they are both produced by monocytes and known to be involved in the pathogenesis of pSS. Methods: Peripheral monocytes were prepared from both pSS patients and normal individuals. The cells were stimulated in vitro with IFN-gamma, and the amounts of IL-6 and sBAFF produced by the cells were quantitated. The effect of sBAFF itself on the production of IL-6 was also studied. To investigate the response of pSS monocytes to these stimuli, the expression levels of the genes encoding BAFF receptors and IL-6-regulating transcription factors were quantitated. Results: Peripheral pSS monocytes produced significantly higher amounts of sBAFF and IL-6 compared to normal monocytes, even in the absence of stimulation. The production of these cytokines was significantly increased upon stimulation with IFN-gamma. The elevated production of IL-6 was significantly suppressed by an anti-BAFF antibody. In addition, stimulation of pSS monocytes with sBAFF induced a significant increase in IL-6 production. Moreover, the expression levels of a BAFF receptor and transcription factors regulating IL-6 were significantly elevated in pSS monocytes compared to normal monocytes. Conclusions: The present study suggests that the mechanisms for the production of sBAFF and IL-6 are impaired in pSS monocytes. Our research implies that this impairment is ascribed to abnormally overexpressed IL-6-regulating transcription factors and a BAFF receptor. These abnormalities may underlie the development of pSS.

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Efficacy and safety of additional use of tacrolimus in patients with early rheumatoid arthritis with inadequate response to DMARDs-a multicenter, double-blind, parallel-group trial

Kawai Shinichi, Takeuchi Tsutomu, Yamamoto Kazuhiko, Tanaka Yoshiya, Miyasaka Nobuyuki

Modern Rheumatology 21 （ 5 ） 458 - 468 2011年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

In this trial, we investigated the safety and efficacy of tacrolimus used in addition to standard antirheumatic drugs in patients with rheumatoid arthritis. Tacrolimus 3 mg or placebo was orally administered once daily for 52 weeks in a double-blind manner to patients with early active rheumatoid arthritis receiving other disease- modifying antirheumatic drugs (DMARDs). A total of 123 patients were randomized to the tacrolimus group (61 patients) and to the placebo group (62 patients). In the tacrolimus group, 70.5% achieved a clinical response according to American College of Rheumatology (ACR) 20 criteria, whereas 45.2% in the placebo group did so (P = 0.005). The tacrolimus group also showed significant improvement in terms of the European League Against Rheumatism (EULAR) response criteria of 'good or moderate' versus the placebo group (86.9 vs. 56.5%, respectively). Likewise, significantly more patients in the tacrolimus group versus the placebo group achieved remission of the Disease Activity Score in 28 joints (DAS28) (45 vs. 21%). The mean changes in the Total Sharp Score and erosion score were lower in the tacrolimus group, but the differences between the two groups were not significant. There was no significant difference between the two groups in the incidence of adverse events. Based on these results, we can conclude that the additional use of tacrolimus in patients with early rheumatoid arthritis with inadequate response to other DMARD treatments is useful, and this could become one of the treatment options for these rheumatoid arthritis patients. © Japan College of Rheumatology 2011.

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Efficacy and Safety of Certolizumab Pegol without Methotrexate Co-Administration in Japanese Patients with Active Rheumatoid Arthritis

竹内勤

ARTHRITIS AND RHEUMATISM 63 （ 10 ） S476 - S476 2011年10月

研究論文（学術雑誌）, ISSN 0004-3591

Clinical, radiographic and functional effectiveness of tocilizumab for rheumatoid arthritis patients-REACTION 52-week study

Takeuchi Tsutomu, Tanaka Yoshiya, Amano Koichi, Hoshi Daisuke, Nawata Masao, Nagasawa Hayato, Sato Eri, Saito Kazuyoshi, Kaneko Yuko, Fukuyo Shunsuke, Kurasawa Takahiko, Hanami Kentaro, Kameda Hideto, Yamanaka Hisashi

Rheumatology 50 （ 10 ） 1908 - 1915 2011年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1462-0324

Objectives: To evaluate the effectiveness and safety of tocilizumab in RA patients in clinical practice. Methods: We observed 232 consecutive RA patients who began tocilizumab in three rheumatology centres in Japan for 52 weeks. Clinical, radiographic and functional status and safety were evaluated. Results: Mean age of the 232 patients was 59.1 years, mean duration of disease was 12.4 years and average DAS using the 28-joint count (DAS-28) was 5.6. Although 62.8% of the patients had been treated previously with anti-TNF biologics, clinical remission at Week 52 was achieved in 43.7%, radiographic non-progression in 62.8% and functional remission in 26.4%. Retention rate at Week 52 was 71.1%, and the same for those with or without previous anti-TNF treatment. Adverse drug reactions leading to tocilizumab discontinuation were observed in 15.5% of patients, the most frequent adverse drug reaction being pneumonia in eight cases. On multivariate logistic regression analysis, DAS-28, HAQ-disability index (HAQ-DI), concomitant MTX and concomitant glucocorticoids (GCs) were predictive variables for clinical remission at Week 52 of tocilizumab treatment. In particular, HAQ-DI was found to be a predictive variable for remission of all three types-clinical, radiographic and functional-at Week 52 of tocilizumab treatment. Conclusions: In daily clinical practice, tocilizumab exhibited excellent effectiveness in established RA patients, some of whom had failed to respond to previous anti-TNF treatment. Although further detailed safety findings are required, this study provides valuable real-world findings on the management of RA with tocilizumab. © The Author 2011. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.

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関節リウマチの診療における労働生産性の評価の意義　より高い治療ゴールのために

竹内勤

リウマチ科 46 （ 3 ） 288 - 296 2011年09月

研究論文（学術雑誌）, 単著

関節リウマチ治療における患者版T2Tリコメンデーション

竹内勤

リウマチ科 46 （ 3 ） 297 - 302 2011年09月

研究論文（学術雑誌）

Continuation of methotrexate resulted in better clinical and radiographic outcomes than discontinuation upon starting etanercept in patients with rheumatoid arthritis

Journal of Rheumatology 38 （ 8 ） 1585 - 1592 2011年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

Objective. The aim of the Efficacy and Safety of Etanercept on Active Rheumatoid Arthritis Despite Methotrexate Therapy in Japan (JESMR) study is to compare the efficacy of continuation versus discontinuation of methotrexate (MTX) when starting etanercept (ETN) in patients with active rheumatoid arthritis (RA). Methods. In total, 151 patients with active RA who had been taking MTX were randomized to either ETN 25 mg twice a week with 6-8 mg/week MTX (the E+M group), or ETN alone (the E group). The primary endpoint at Week 52 was the radiographic progression assessed by van der Heijde-modified Sharp score. Results. The mean progression in total score at Week 52 was not significantly different, statistically, between the E+M group and the E group (0.8 vs 3.6, respectively; p = 0.06). However, a significant difference was observed in radiographic progression between Weeks 24 and 52 (0.3 vs 2.5; p = 0.03), and the mean progression of the erosion score was negative in the E+M group, which was significantly better than the E group at Week 52 (-0.2 vs 1.8; p = 0.02). Clinically, the cumulative probability plot of the American College of Rheumatology (ACR)-N values at Week 52 clearly demonstrated a superior response in the E+M group than in the E group. ACR20, 50, and 70 response rates at Week 52 in the E+M group (86.3%, 76.7%, and 50.7%) were significantly greater than those in the E group (63.8%; p = 0.003, 43.5%; p < 0.0001 and 29.0%; p = 0.01, respectively). Conclusion. MTX should be continued when starting ETN in patients with active RA. The Journal of Rheumatology Copyright © 2011. All rights reserved.

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

Koike Takao, Harigai Masayoshi, Inokuma Shigeko, Ishiguro Naoki, Ryu Junnosuke, Takeuchi Tsutomu, Tanaka Yoshiya, Yamanaka Hisashi, Fujii Koichi, Yoshinaga Takunari, Freundlich Bruce, Suzukawa Michio

Modern Rheumatology 21 （ 4 ） 343 - 351 2011年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Our aim was to evaluate real-world safety and effectiveness in a 6-month postmarketing surveillance study covering all Japanese patients with rheumatoid arthritis (RA) who received etanercept during a 2-year period. Data for 13,894 patients (1334 sites) enrolled between March 2005 and April 2007 were collected. Adverse events (AEs) and serious adverse events (SAEs) were reported in 4336 (31.2%) and 857 (6.2%) patients, respectively. The most frequent AEs were injection site reactions (n = 610, 4.4%) and rash (n = 339, 2.4%), whereas pneumonia (n = 116, 0.8%) and interstitial lung disease (n = 77, 0.6%) were the most frequent SAEs. Significant improvement in the proportion of patients with a good European League Against Rheumatism (EULAR) response was observed from week 4 (17.6%) to week 24 (31.6%) (p<0.001); 84.3% of patients had good or moderate EULAR responses at week 24. The percentage of patients achieving remission increased significantly from week 4 (9.3%) to week 24 (18.9%) (p<0.001). Patients with early moderate RA were less likely to experience SAEs and were more likely to achieve remission compared with patients with more severe disease. The safety and effectiveness of etanercept was demonstrated in Japanese patients in one of the largest observational trials conducted thus far in RA patients treated with biologics. © Japan College of Rheumatology 2011.

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Baseline tumour necrosis factor alpha levels predict the necessity for dose escalation of infliximab therapy in patients with rheumatoid arthritis

Takeuchi Tsutomu, Miyasaka Nobuyuki, Tatsuki Yoshihiko, Yano Toshiro, Yoshinari Toru, Abe Tohru, Koike Takao

Annals of the Rheumatic Diseases 70 （ 7 ） 1208 - 1215 2011年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

Objectives: To investigate the possible role of baseline plasma tumour necrosis factor alpha levels (baseline-TNF) on the clinical response to infliximab in patients with rheumatoid arthritis (RA). Methods: Patients with RA refractory to methotrexate received 3, 6, or 10 mg/kg of infliximab every 8 weeks, in a randomised, double-blind manner: the RISING study. Clinical response (disease activity score in 28 joints based on C-reactive protein or American College of Rheumatology core set) at week 54 and serum infliximab levels were compared in three patient groups with low, intermediate, or high baseline-TNF (TNF-low, TNF-int, or TNF-high). Results: In TNF-low patients, the clinical response to different doses of infliximab was comparable, whereas TNF-int patients exhibited a dose-dependent trend. In contrast, TNF-high patients (approximately 13% of the total patients) had a clinical response to 10 mg/kg significantly better than the response to 3 and 6 mg/kg of infliximab. In TNF-high patients, the median trough serum levels of infliximab were below the detection limit (<0.1 μg/ml) at 3 and 6 mg/kg but were greater than 2 μg/ml at 10 mg/kg, whereas the levels were approximately 1 μg/ml for each dosage group in TNF-low patients. Conclusion: In patients with RA, baseline-TNF is significantly associated with the clinical response to infliximab in patients with a high baseline-TNF. A higher dose of infliximab may be necessary in these patients, whereas lower doses of infliximab are sufficient for those with a low baseline-TNF. Baseline-TNF may be a useful measure for personalising the treatment of RA using infliximab.

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Sensitivity and specificity of 2010 rheumatoid arthritis classification criteria

竹内勤

RHEUMATOLOGY 50 （ 7 ） 1268 - 1274 2011年07月

研究論文（学術雑誌）, ISSN 1462-0324

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Incidence and risk factors for serious infection in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors

Komano Yukiko, Tanaka Michi, Nanki Toshihiro, Koike Ryuji, Sakai Ryoko, Kameda Hideto, Nakajima Atsuo, Saito Kazuyoshi, Takeno Mitsuhiro, Atsumi Tatsuya, Tohma Shigeto, Ito Satoshi, Tamura Naoto, Fujii Takao, Sawada Tetsuji, Ida Hiroaki, Hashiramoto Akira, Koike Takao, Ishigatsubo Yoshiaki, Eguchi Katsumi, Tanaka Yoshiya, Takeuchi Tsutomu, Miyasaka Nobuyuki, Harigai Masayoshi

Journal of Rheumatology 38 （ 7 ） 1258 - 1264 2011年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

Objective. To compare tumor necrosis factor-α (TNF-α) inhibitors to nonbiological disease-modifying antirheumatic drugs (DMARD) for the risk of serious infection in Japanese patients with rheumatoid arthritis (RA). Methods. Serious infections occurring within the first year of the observation period were examined using the records for patients recruited to the Registry of Japanese Rheumatoid Arthritis Patients for Longterm Safety (REAL), a hospital-based prospective cohort of patients with RA. The analysis included 1144 patients, 646 of whom were treated with either infliximab or etanercept [exposed group: 592.4 patient-years (PY)]. The remaining 498 patients received nonbiological DMARD with no biologics (unexposed group: 454.7 PY). Results. In the unexposed group, the incidence rate for all serious adverse events (SAE) was 9.02/100 PY and for serious infections, 2.64/100 PY. In the exposed group, SAE occurred in 16.04/100 PY and serious infections in 6.42/100 PY. The crude incidence rate ratio comparing serious infections in the exposed group with the unexposed group was 2.43 (95% CI 1.27-4.65), a significant increase. A multi variate analysis revealed that the use of TNF inhibitors is a significant independent risk factor for serious infection (relative risk 2.37, 95% CI 1.11-5.05, p = 0.026). Conclusion. Our study has provided the first epidemiological data on Japanese patients with RA for the safety of TNF inhibitors compared to nonbiological DMARD for up to 1 year of treatment. Anti-TNF therapy was associated with a significantly increased risk for serious infections, compared to treatment with nonbiological DMARD.

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Single center prospective study of tacrolimus efficacy and safety in the treatment of various manifestations in systemic lupus erythematosus

Suzuki Katsuya, Kameda Hideto, Amano Koichi, Nagasawa Hayato, Takei Hirofumi, Nishi Eiko, Okuyama Ayumi, Tsuzaka Kensei, Takeuchi Tsutomu

Rheumatology International 31 （ 6 ） 757 - 763 2011年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0172-8172

The aim of this study was to prospectively evaluate the efficacy and safety of tacrolimus (TAC) in various manifestations of systemic lupus erythematosus (SLE) patients in daily clinical practice. Each of the 21 TAC-treated patients with SLE in our care over 2 years was enrolled in this open-label trial. Patients were administered TAC at a dosage of 1-6 mg once daily, followed up for 24 weeks. Efficacy and safety were evaluated utilizing clinical and laboratory findings. As treatment targets, TAC was preferentially used with oral corticosteroid administration for mild active manifestations such as arthritis, skin eruptions, or asymptomatic nephritis. In efficacy, the mean value of the SLE disease activity index was significantly reduced to 4.1, 2.7, 1.8, and 1.2 (N = 21, 20, 16 and 13) at 0, 4, 12, and 24 weeks, respectively. In eight cases, treatment was discontinued within 24 weeks due to insufficient effects (6 cases) and side effects (2 cases). Non-serious side effects were observed in only five cases (23.8%) over 24 weeks. TAC can be considered both effective and safe for the treatment of various manifestations of SLE. © 2010 Springer-Verlag.

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Revolutionary change in rheumatoid arthritis management with biological therapy

Takeuchi Tsutomu

Keio Journal of Medicine 60 （ 3 ） 75 - 81 2011年06月

研究論文（学術雑誌）, 単著, 査読有り, ISSN 0022-9717

Biological agents targeting a specific molecule have extraordinarily fine specificity and powerful functional capabilities. By the introduction of biological therapy, management of rheumatoid arthritis has undergone a revolution and a paradigm shift. In this review, I will summarize the role in the pathogenesis of rheumatoid arthritis of the molecules targeted by biological agents. Providing evidence obtained in clinical trials and investigator-initiated clinical studies in Japan, the effectiveness and safety of biological therapy in rheumatoid arthritis are discussed. Finally, studies aiming at a personalized strategy with biological agents are listed and the future perspectives toward tailor-made medicine in the field of rheumatology are discussed. © 2011 by The Keio Journal of Medicine.

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Efficacy and tolerability of tocilizumab in rheumatoid arthritis patients seen in daily clinical practice in Japan

Yamanaka Hisashi, Tanaka Yoshiya, Inoue Eisuke, Hoshi Daisuke, Momohara Shigeki, Hanami Kentaro, Yunoue Naoki, Saito Kazuyoshi, Amano Kouichi, Kameda Hideto, Takeuchi Tsutomu

Modern Rheumatology 21 （ 2 ） 122 - 133 2011年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Tocilizumab, a humanized monoclonal antibody to the interleukin 6 (IL-6) receptor, was approved for use as rheumatoid arthritis (RA) therapy in Japan in 2008, but its efficacy and tolerability in daily practice has not yet been reported. We report the results of a multicenter retrospective study on the efficacy and safety of tocilizumab involving all patients (n = 229) who were started on tocilizumab therapy at three rheumatology institutes in Japan from April 2008 through to March 2009. Tocilizumab was infused every 4 weeks at a dose of 8 mg/kg according to the drug labeling. Among the 229 patients, 55% concomitantly received methotrexate (MTX) and 63% had previously received anti-tumor necrosis factor (TNF) therapy. Average disease activity score (DAS) 28 of all 229 patients significantly decreased from 5.70 to 3.25 after 24 weeks of therapy. A European League Against Rheumatism (EULAR) good response and DAS28 remission was achieved in 57.4 and 40.7% of the patients, respectively, at 24 weeks. White blood cell counts significantly decreased and liver enzymes and total cholesterol slightly but significantly increased; however, liver enzyme levels did not increase in patients without MTX. Tocilizumab was discontinued in 47 cases (20.5%) due to lack of efficacy (5.2%), adverse events (11.4%), and other reasons (3.9%). The overall retention rate at 24 weeks was 79.5%. Based on these results, we conclude that tocilizumab therapy in daily rheumatology practice appears to be highly efficacious and well tolerated among active RA patients, including the anti-TNF therapy-refractory population. Tocilizumab infusion is therefore applicable not only as an alternative approach for anti-TNF therapy-resistant patients, but also as primary biologic therapy for active RA patients. © Japan College of Rheumatology 2010.

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Fcγ receptor IIIb polymorphism and use of glucocorticoids at baseline are associated with infusion reactions to infliximab in patients with rheumatoid arthritis

Okuyama Ayumi, Nagasawa Hayato, Suzuki Katsuya, Kameda Hideto, Kondo Harumi, Amano Kouichi, Takeuchi Tsutomu

Annals of the Rheumatic Diseases 70 （ 2 ） 299 - 304 2011年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

Objective: Infusion reaction is a major adverse event in patients with rheumatoid arthritis (RA) treated with infliximab. The possible factors including Fcγ receptor (FcγR) polymorphism associated with the development of infusion reactions in patients with RA receiving infliximab were prospectively examined. Methods: 96 patients with RA were enrolled and scheduled to receive infliximab at a dose of 3 mg/kg at weeks 0, 2 and 6 and every 8 weeks thereafter. Genetic polymorphisms for FcγR were examined in FCGR3A 176F/V and FCGR3B NA1/2 alleles by allele-specific PCR analysis. Results: An infusion reaction was observed in 17 patients (18%) during 52 weeks of treatment with infliximab. The FCGR3B NA1/NA1 genotype was found in 75% of the patients with infusion reactions and in only 37% of those without (p=0.01), whereas the FCGR3A 176F/V genotype was equally distributed in the patients with or without infusion reactions. Glucocorticoids were used in 53% of the patients who developed an infusion reaction and in 80% of those without an infusion reaction (p=0.02). A multivariable logistic regression model showed that the FCGR3B NA1/NA1 genotype and use of glucocorticoids at baseline could be used as independent predictive factors for infusion reactions (OR 6.1 (95% CI 1.9 to 24.3) and OR 0.26 (95% CI 0.08 to 0.84), respectively). The presence of anti-infliximab antibody during infliximab treatment was also associated with infusion reactions. Conclusion: FCGR3B NA1/NA1 genotype, use of glucocorticoids and the presence of anti-infliximab antibody accounted for nearly all patients with RA who developed infusion reactions.

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Humanized anti-IL-6R antibody (tocilizumab) monotherapy is more effective in slowing radiographic progression in patients with rheumatoid arthritis at high baseline risk for structural damage evaluated with levels of biomarkers, radiography, and BMI

Hashimoto Jun, Garnero Patrick, Van Der Heijde Désirée, Miyasaka Nobuyuki, Yamamoto Kazuhiko, Kawai Shinichi, Takeuchi Tsutomu, Yoshikawa Hideki, Nishimoto Norihiro

Modern Rheumatology 21 （ 1 ） 10 - 15 2011年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Our aim was to assess the ability of tocilizumab monotherapy to reduce progressive structural joint damage in rheumatoid arthritis patients at high risk of progression. This study was a subanalysis from a prospective 1-year, multicenter, X-ray-reader-blinded, randomized controlled trial of tocilizumab [Study of Active Controlled Monotherapy Used for Rheumatoid Arthritis, an IL-6 Inhibitor (SAMURAI) trial]. All patients were categorized into two or three groups according to four independent predictive markers for progressive joint damage [urinary C-terminal crosslinking telopeptide (uCTX-II), urinary pyridinoline/deoxypyridinoline (uPYD/DPD) ratio, body mass index (BMI), and joint-space narrowing (JSN) score at baseline]. One-year progression of joint destruction was assessed in high-risk versus low-risk groups receiving tocilizumab monotherapy and compared with patients receiving conventional disease-modifying antirheumatic drugs (DMARDs) (n = 157 and 145, respectively). In patients at high risk of progression of erosion as estimated by high uCTX-II, uPYD/DPD, or low BMI, and at high risk of progression of JSN as estimated by low BMI or high JSN score, the 52-week changes in radiological erosion and JSN, respectively, were significantly less in patients treated with tocilizumab monotherapy compared with those receiving DMARDs for each type of risk factor. In patients at low risk, those receiving tocilizumab also progressed less than those on DMARDs, although the difference did not reach statistical significance. Tocilizumab monotherapy is more effective in reducing radiological progression in patients presenting with risk factors for rapid progression than in low-risk patients. Patients at high risk for progression may benefit more from tocilizumab treatment. © 2010 Japan College of Rheumatology.

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Decreased mrna expression of two FOXP3 isoforms in peripheral blood mononuclear cells from patients with rheumatoid arthritis and systemic lupus erythematosus

Suzuki K., Setoyama Y., Yoshimoto K., Tsuzaka K., Abe T., Takeuchi Tsutomu

International Journal of Immunopathology and Pharmacology 24 （ 1 ） 7 - 14 2011年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0394-6320

Both the number and functional capacity of T-regulatory (Treg) cells are known to be decreased in various autoimmune diseases. FOXP3, an essential transcription factor for Treg cells, has three isoforms in humans, wild, and exon 2- and exon 2-exon 7-lacking, although their role in autoimmunity is not clearly understood. Here, we investigated the messenger RNA (mRNA) expression of the major wild and exon-2 isoforms in peripheral mononuclear cells by quantitative PCR methods in 56 subjects, consisting of 23 rheumatoid arthritis (RA) and 25 systemic lupus erythematosus (SLE) patients, and 8 healthy controls (HCs). Although mRNA expression of the two isoforms did not directly correlate with clinical disease activity, relative expression of both was significantly lower in SLE and RA patients than in HCs. Furthermore, we found a significant statistical correlation between the two isoforms, suggesting that they are similarly regulated. Decreased expression of these isoforms in RA and SLE may reflect Treg cell abnormalities in these autoimmune diseases. Copyright © by BIOLIFE, s.a.s.

DECREASED mRNA EXPRESSION OF TWO FOXP3 ISOFORMS IN PERIPHERAL BLOOD MONONUCLEAR CELLS FROM PATIENTS WITH RHEUMATOID ARTHRITIS AND SYSTEMIC LUPUS ERYTHEMATOSUS

竹内勤

International Journal of Immunopathology and Pharmacology 24 （ 1 ） 7 - 14 2011年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0394-6320

Microscopic polyangitis complicating double carcinoma of the stomach and duodenum

Abe Haruo, Momose Shuji, Takeuchi Tsutomu

Rheumatology International 31 （ 1 ） 105 - 108 2011年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0172-8172

A 74-year-old woman developed fever, numbness of legs and glomerulonephritis. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase (MPO-ANCA) were positive in her serum, and she presented with acute renal failure. She was also simultaneously diagnosed as having both gastric and duodenal cancers. Complete resection of both cancers and renal biopsy was performed. Some glomeruli showed cellular crescentic changes, while submucosal necrotizing vasculitis of small vessels was noted adjacent to the gastric cancer. A diagnosis of microscopic polyangitis was made. After the operation, the patient's fever, renal failure and microscopic hematuria improved and obvious reductions in her serum soluble receptors of interleukin 2 values and MPO-ANCA titer were observed without any further treatment. However, the patient's proteinuria, cylinduria, and elevated C-reactive protein persisted; these findings eventually resolved after treatment with 30 mg of prednisolone daily. An immunohistochemical analysis showed that CD8 T lymphocytes had infiltrated both the carcinomas and the renal lesions. Our case suggests that CD8 T cells induced as part of an immune response against carcinoma may play a pathologic role in ANCA-positive paraneoplastic syndrome. © 2009 Springer-Verlag.

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Clinical and radiological features of acute-onset diffuse interstitial lung diseases in patients with rheumatoid arthritis receiving treatment with biological agents

Kameda Hideto, Tokuda Hitoshi, Sakai Fumikazu, Johkoh Takeshi, Mori Shunsuke, Yoshida Yuji, Takayanagi Noboru, Taki Hirofumi, Hasegawa Yoshinori, Hatta Kazuhiro, Yamanaka Hisashi, Dohi Makoto, Hashimoto Shu, Yamada Hidehiro, Kawai Shinichi, Takeuchi Tsutomu, Tateda Kazuhiro, Goto Hajime

Internal Medicine 50 （ 4 ） 305 - 313 2011年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0918-2918

Objective Acute-onset diffuse interstitial lung disease (AoDILD) in patients with rheumatoid arthritis (RA) has been a serious concern, especially for those under treatment with biological agents which may affect the presentation and outcome of AoDILD, including Pneumocystis pneumonia (PCP). Therefore, we conducted a retrospective, multi-center study of AoDILD in RA patients receiving biological agents. Methods Patients who developed AoDILD while receiving biological agents (infliximab, etanercept, adalimumab and tocilizumab) were enrolled in the study. Definite PCP was defined as patients who showed either P. jirovecii organisms in their respiratory samples by microscopic examination, or positive tests for both P. jirovicii DNA-PCR with respiratory samples and an elevated serum 1,3-β-D-glucan level above the cut-off value. Probable PCP was defined as either a positive test for P. jirovicii PCR or an elevated serum β-D-glucan level. Chest HRCT findings were evaluated and scored by two board-certified radiologists. Results The final diagnoses for 26 patients examined were definite PCP for 13 patients, probable PCP for 11, and methotrexate-associated pneumonitis in 2 patients. Definite and probable PCP cases were clinically indistinguishable. Generalized, diffuse ground-glass opacity (GGO) is the characteristic HRCT finding in patients with definite or probable PCP, which was different from our previous findings in RA patients, mostly without biologics, showing GGO distributed in a panlobular or multilobular manner. The clinical outcome was favorable by treatment with trimethoprim-sulfamethoxazole and glucocorticoids. Conclusion The possibility of PCP should be intensively investigated in RA patients developing AoDILD while receiving biological agents. © 2011 The Japanese Society of Internal Medicine.

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Etanercept (ETN) with methotrexate (MTX) is better than ETN monotherapy in patients with active rheumatoid arthritis despite MTX therapy

Kameda Hideto, Ueki Yukitaka, Saito Kazuyoshi, Nagaoka Shouhei, Hidaka Toshihiko, Atsumi Tatsuya, Tsukano Michishi, Kasama Tsuyoshi, Shiozawa Shunichi, Tanaka Yoshiya, Takeuchi Tsutomu

Modern Rheumatology 20 （ 6 ） 531 - 538 2010年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

The superiority of the combination therapy of methotrexate (MTX) and anti-tumor necrosis factor (TNF) biological agents over anti-TNF monotherapy in MTX-naïve patients with rheumatoid arthritis (RA) has been demonstrated. We investigated the efficacy and safety of continuation versus discontinuation of MTX at the commencement of etanercept (ETN) in patients with active RA despite MTX therapy. In total, 151 patients with active RA despite treatment with MTX were randomized to either ETN 25 mg twice a week and MTX 6-8 mg/week (the E + M group) or ETN alone (the E group). Co-primary endpoints included the European League Against Rheumatism (EULAR) good response rate and the American College of Rheumatology (ACR) 50 response rate at week 24. Demographic and clinical features between groups at baseline were similar. The EULAR good response rates were significantly higher in the E + M group (52%) than in the E group (33%) at week 24 (p = 0.0001). Although the ACR50 response rate, one of the co-primary endpoints, and the ACR70 response rate at week 24 were not significantly greater in the E + M group (64 and 38%, respectively) than in the E group (48 and 26%, respectively), the ACR20 response rate was significantly greater in the E + M group (90%) than in the E group (64%; p = 0.0002). Safety profiles were similar for the groups. Thus, MTX should be continued at the commencement of ETN therapy, even in RA patients who show an inappropriate response to MTX. © 2010 Japan College of Rheumatology.

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The Japanese experience with biologic therapies for rheumatoid arthritis

竹内勤

Nature Reviews Rheumatology 6 （ 11 ） 644 - 652 2010年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1759-4790

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Differences between the Health Assessment Questionnaire Disability Index (HAQ-DI) and the modified HAQ (mHAQ) score before and after infliximab treatment in patients with rheumatoid arthritis.

Nagasawa Hayato, Kameda Hideto, Sekiguchi Naoya, Amano Koichi, Takeuchi Tsutomu

Modern rheumatology / the Japan Rheumatism Association 20 （ 4 ） 337 - 342 2010年08月

研究論文（学術雑誌）, 共著, 査読有り

We conducted a 1-year prospective study to clarify differences between the Health Assessment Questionnaire disability index (HAQ-DI) and the modified HAQ (mHAQ) score among rheumatoid arthritis (RA) patients treated with infliximab. A total of 87 patients were scheduled to receive infliximab infusion at a dose of 3 mg/kg at weeks 0, 2, and 6, and every 8 weeks thereafter for 54 weeks; all patients received a full examination at each infusion appointment. The 28-joint disease activity score (DAS28) and functional capability of each patient was assessed at each visit, using the HAQ-DI and the mHAQ score. A strong correlation was observed between the HAQ-DI and the mHAQ score at baseline (r = 0.892). Over the course of the treatment, the mean mHAQ score changed similarly to the HAQ-DI, but the mean HAQ-DI was significantly higher than the mean mHAQ score at each time-point (for the HAQ-DI vs. mHAQ score, baseline: 1.5 +/- 0.7 vs. 0.9 +/- 0.6, p < 0.0001; 6 weeks: 1.1 +/- 0.7 vs. 0.6 +/- 0.5, p < 0.0001; 30 weeks: 1.0 +/- 0.7 vs. 0.6 +/- 0.5, p < 0.0001; 54 weeks: 0.9 +/- 0.7 vs. 0.6 +/- 0.6, p = 0.0006). In the categories of "eating", "reaching", and "other activities", the scores for several items excluded from the mHAQ score were significantly higher than those included in the mHAQ score over the year-long study period. We identified items contributing to significant differences between the HAQ-DI and the mHAQ score among RA patients treated with infliximab.

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ADAMTS5 is a biomarker for prediction of response to infliximab in patients with rheumatoid arthritis

Tsuzaka Kensei, Itami Yuka, Takeuchi Tsutomu, Shinozaki Naoshi, Morishita Tetsuo

Journal of Rheumatology 37 （ 7 ） 1454 - 1460 2010年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

Objective. To identify a biomarker for prediction of the response to infliximab (IFX) in patients with rheumatoid arthritis (RA), we focused on a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) that seems to play a key role in aggrecan degradation in cartilage. Methods. Seventy-three randomly selected patients with active RAwere treated with IFX. Peripheral blood samples were collected at baseline and ADAMTS5 messenger RNA (mRNA) was quantified using real-time polymerase chain reaction. Results. Baseline ADAMTS5 mRNA levels in the good responder group were significantly lower (1.84 ± 1.56; p = 0.0408) than those in the moderate and nonresponder groups (2.54 ± 1.70) at 38 weeks of treatment with IFX. The 28-joint count Disease Activity Score (DAS28) at 38 weeks of treatment was significantly lower in the low ADAMTS5 group (2.30 ± 1.28; p = 0.0038) than in the high ADAMTS5 group (3.90 ± 1.61). The percentage reduction of the DAS28 was significantly higher in the low ADAMTS5 group (52.5% ± 28.8%; p = 0.0156) than in the high ADAMTS5 group (29.4% ± 27.2%). Further, the Δ Health Assessment Questionnaire (ΔHAQ) score, an estimate of the improvement in the HAQ score, at 38 weeks of treatment was significantly higher in the low ADAMTS5 group (1.18 ± 0.60; p = 0.0102) than in the high ADAMTS5 group (0.21 ± 0.78). The positive predictive value of a low baseline ADAMTS5 level for predicting good response and remission (DAS28 < 2.6 at 38 weeks) was 90.0% and 70.0%, respectively. Conclusion. The baseline ADAMTS5 mRNA level is a candidate biomarker for prediction of the response to IFX in patients with RA. The Journal of Rheumatology Copyright © 2010. All rights reserved.

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Discontinuation of infliximab after attaining low disease activity in patients with rheumatoid arthritis

Tanaka Y., Takeuchi T., Mimori T., Saito K., Nawata M., Kameda H., Nojima T., Miyasaka N., Koike T.

Annals of the Rheumatic Diseases 69 （ 7 ） 1286 - 1291 2010年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

Background: Tumour necrosis factor (TNF) inhibitors enable tight control of disease activity in patients with rheumatoid arthritis (RA). Discontinuation of TNF inhibitors after acquisition of low disease activity (LDA) is important for safety and economic reasons. Objective: To determine whether infliximab might be discontinued after achievement of LDA in patients with RA and to evaluate progression of articular destruction during the discontinuation. Methods: 114 patients with RA who had received infliximab treatment, and whose Disease Activity Score, including a 28-joint count (DAS28) was <3.2 (LDA) for 24 weeks, were studied. Results: The mean disease duration of the 114 patients was 5.9 years, mean DAS28 5.5 and mean modified total Sharp score (mTSS) 63.3. After maintaining LDA for >24 weeks by infliximab treatment, the drug was discontinued and DAS28 in 102 patients was evaluated at year 1. Fifty-six patients (55%) continued to have DAS28<3.2 and 43% reached DAS<2.6 at 1 year after discontinuing infliximab. For 46 patients remission induction by Remicade in RA (RRR) failed: disease in 29 patients flared within 1 year and DAS28 was >3.2 at year 1 in 17 patients. Yearly progression of mTSS (ΔTSS) remained <0.5 in 67% and 44% of the RRR-achieved and RRR-failed groups, respectively. The estimated ΔmTSS was 0.3 and 1.6 and Health Assessment Questionnaire-Disability Index was 0.174 and 0.614 in the RRR-achieved and RRR-failed groups, respectively, 1 year after the discontinuation. Conclusion: After attaining LDA by infliximab, 56 (55%) of the 102 patients with RA were able to discontinue infliximab for >1 year without progression of radiological articular destruction.

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IgG4-positive multi-organ lymphoproliferative syndrome manifesting as chronic symmetrical sclerosing dacryo-sialadenitis with subsequent secondary portal hypertension and remarkable IgG4-linked IL-4 elevation

Suzuki Katsuya, Tamaru Jun Ichi, Okuyama Ayumi, Kameda Hideto, Amano Koichi, Nagasawa Hayato, Nishi Eiko, Yoshimoto Keiko, Setoyama Yumiko, Kaneko Keiko, Osada Hisato, Honda Norinari, Sasaki Yasutsuna, Itoyama Shinji, Tsuzaka Kensei, Takeuchi Tsutomu

Rheumatology 49 （ 9 ） 1789 - 1791 2010年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1462-0324

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Efficacy and safety of cyclosporine A in patients with refractory systemic lupus erythematosus in a daily clinical practice

Ogawa H., Kameda H., Amano K., Takeuchi T.

Lupus 19 （ 2 ） 162 - 169 2010年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0961-2033

We investigated the efficacy and safety of cyclosporine A (CsA; targeted serum trough level: 80-150 ng/ml) in a daily clinical practice for treating patients with systemic lupus erythematosus (SLE), who had been, or were expected to be, refractory to glucocorticoids (GCs) and other immunosuppressants. Fifty-nine patients with SLE receiving CsA were observed for at least 6 months (21.5 months on average). A significant reduction of proteinuria was noted 2 weeks after initiation of treatment in patients with nephritis, resulting in a clinical response in five of eight patients in the GC dose-up group and 11 of 18 patients in the stable GC dose group, respectively. Notably, the mean score for disease activity on the SLE Disease Activity Index decreased significantly from 8.6 ± 5.3 to 4.4 ± 2.5 after CsA treatment in patients in the stable GC dose group (n = 40). Moreover, the mean flare rate decreased by approximately 60% with CsA. Side effects of CsA appeared in 32.2% of patients and all of them subsided through dose reduction or discontinuation (n=8) of CsA. Consequently, the cumulative 2-year survival rate of CsA was 75%. The results suggest that CsA should be considered for patients with SLE refractory to GCs. Lupus (2010) 19, 162-169.

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CLINICAL AND IMMUNOLOGICAL CHARACTERISTICS OF JAPANESE PATIENTS WITH CONNECTIVE TISSUE DISEASE AND PULMONARY ARTERIAL HYPERTENSION

竹内勤

Clinical and Experimental Rheumatology 28 （ 2 ） S125 - S126 2010年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0392-856X

Reduced expression of TCR zeta is involved in the abnormal production of cytokines by peripheral T cells of patients with systemic lupus erythematosus

Yoshimoto Keiko, Setoyama Yumiko, Tsuzaka Kensei, Abe Tohru, Takeuchi Tsutomu

Journal of Biomedicine and Biotechnology 2010 6 2010年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1110-7243

Accumulating evidence suggests that dysfunction of T cells underlies the pathogenesis of systemic lupus erythematosus (SLE). We revealed that SLE T cells produced an abnormally excessive amount of IFN- in vitro upon stimulation through TCR, and the expression level of TCR zeta was significantly reduced. The production of IFN- by SLE T cells was negatively correlated with the expression level of TCR zeta. This correlation was abolished when the cells were stimulated with TPA and ionomycin, which bypass TCR and introduce signals directly into the cells, but the production of IFN- by SLE T cells remained abnormally elevated. Taken together, these data suggest that regulatory mechanisms not only for the expression of TCR zeta but also for the production of IFN- were impaired in SLE T cells. These impairments may be responsible for the aberrant responses of SLE T cells and partly involved in the development of SLE. © 2010 Keiko Yoshimoto et al.

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Normalisation of physical function by infliximab in patients with RA

Nagasawa Hayato, Kameda Hideto, Sekiguchi Naoya, Amano Koichi, Takeuchi Tsutomu

Clinical and Experimental Rheumatology 28 （ 3 ） 365 - 372 2010年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0392-856X

Objectives: We conducted a two-year prospective study to identify possible factors associated with normalisation of physical function by infliximab treatment in 125 patients with rheumatoid arthritis (RA). Methods RA patients who had been scheduled to receive infliximab at 3 mg/kg were registered and prospectively examined for disease activity, joint damage, and physical function for 102 weeks using the Disease Activity Score of 28 Joints (DAS-28) using C-reactive protein, van der Heijde-modified Sharp score (vdH-Sharp score) of hand and foot x-ray, and Health Assessment Questionnaire Disability Index (HAQ-DI). Normal physical function and clinical remission were defined as a HAQ-DI of 0.5 or less, and DAS28 (CRP) <2.6, respectively. Results: Forty-two of 125 patients (42%) achieved normal physical function at 102 weeks. The percentage of normal physical function at 102 weeks was significantly higher in the patients achieving clinical remission at 102 weeks (60%) than in those without (16%). In the patients with clinical remission at 102 weeks, less structural damage at baseline was correlated with a higher rate of normal physical function, suggesting the critical importance of joint destruction prior to infliximab therapy, in addition to clinical response. Logistic regression analysis further identified HAQ-DI, serum MMP-3 level, vdH-Sharp score, and methotrexate (MTX) dose as baseline factors contributing to normal physical function with 2-year infliximab treatment. Conclusion: Treatment with anti-TNF biologics in combination with MTX may achieve the normalisation of physical function in patients with established RA. Critical factors contributing to the normalisation of function were tight control of disease activity and less joint damage. © Copyright Clinical and Experimental Rheumatology 2010.

Long-term safety and efficacy of tocilizumab, an anti-IL-6 receptor monoclonal antibody, in monotherapy, in patients with rheumatoid arthritis (the STREAM study)

Nishimoto N., Miyasaka N., Yamamoto K., Kawai S., Takeuchi T., Azuma J.

Annals of the Rheumatic Diseases 68 （ 10 ） 1580 - 1584 2009年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

Objectives: To evaluate the safety and efficacy of 5-year, long-term tocilizumab monotherapy for patients with rheumatoid arthritis. Methods: In an open-label, long-term extension trial following an initial 3-month randomised phase II trial, 143 of the 163 patients who participated in the initial blinded study received tocilizumab monotherapy (8 mg/kg) every 4 weeks. Concomitant therapy with non-steroidal anti-inflammatory drugs and/or oral prednisolone (10 mg daily maximum) was permitted. All patients were evaluated with American College of Rheumatology (ACR) improvement criteria, disease activity score (DAS) in 28 joints, and the European League Against Rheumatism response, as well as for safety issues. Results: 143 patients were enrolled in the open-label, long-term extension trial and 94 (66%) patients had completed 5 years as of March 2007. 32 patients (22%) withdrew from the study due to adverse events and one patient (0.7%) due to unsatisfactory response. 14 patients withdrew because of the patient's request or other reasons. The serious adverse event rate was 27.5 events per 100 patient-years, with 5.7 serious infections per 100 patient-years, based on a total tocilizumab exposure of 612 patient-years. Of the 88 patients receiving corticosteroids at baseline, 78 (88.6%) were able to decrease their corticosteroid dose and 28 (31.8%) discontinued corticosteroids. At 5 years, 79/94 (84.0%), 65/94 (69.1%) and 41/94 (43.6%) of the patients achieved ACR20, ACR50, and ACR70 improvement criteria, respectively. Remission defined as DAS28 less than 2.6 was achieved in 52/94 (55.3%) of the patients. Conclusion: In this 5-year extension study, tocilizumab demonstrated sustained long-term efficacy and a generally good safety profile.

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Factors associated with fatal outcome of leflunomide-induced lung injury in Japanese patients with rheumatoid arthritis.

Sato Takeo, Inokuma Shigeko, Sagawa Akira, Matsuda Takemasa, Takemura Tamiko, Otsuka Takeshi, Saeki Yukihiko, Takeuchi Tsutomu, Sawada Tetsuji

Rheumatology (Oxford, England) 48 （ 10 ） 1265 - 1268 2009年10月

研究論文（学術雑誌）, 共著, 査読有り

OBJECTIVE: To elucidate the factors associated with poor prognosis of LEF-induced lung injury in patients with RA. METHODS: The background and clinical and laboratory features of LEF-induced lung injury were examined and compared between patients who died of and who recovered from it. RESULTS: Among 22 patients who developed LEF-induced lung injury, 9 died of and 13 recovered from it. The patients who died tended to have pre-existing interstitial pneumonia (8/9 vs 6/13, P = 0.07). The loading and maintenance doses, serum concentration of the LEF metabolite A771726 and administration period did not differ between the groups. Patients who died had more frequently hypoxaemia of <60 Torr and mechanical ventilation, and had a high serum CRP level (19.3 +/- 9.4 vs 10.1 +/- 8.1 mg/dl, P = 0.03) and a low albumin level (2.7 +/- 0.6 vs 3.3 +/- 0.5 g/dl, P = 0.03) at the lung injury onset. The peripheral blood lymphocyte count decreased in both groups at the lung injury onset, and it remained low until fatal outcome, in contrast to a re-increase upon recovery (406 +/- 394 vs 1203 +/- 399/microl, P = 0.006). The main histopathological finding in two autopsied patients was diffuse alveolar damage, in contrast to the alveolitis observed in a biopsied patient who recovered. CONCLUSIONS: Pre-existing interstitial pneumonia, extremely high serum CRP and low albumin levels, severe hypoxaemia and mechanical ventilation indicated poor prognosis. Peripheral blood lymphocytopenia developed in association with lung injury, and a sustained low lymphocyte count indicated a fatal outcome.

Leflunomide-induced interstitial lung disease

Sawada Tetsuji, Inokuma Shigeko, Sato Takeo, Otsuka Takeshi, Saeki Yukihiko, Takeuchi Tsutomu, Matsuda Takemasa, Takemura Tamiko, Sagawa Akira

Rheumatology 48 （ 9 ） 1069 - 1072 2009年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1462-0324

Objective: The possible link between LEF and interstitial lung disease (ILD) has evoked increasing concern. The aim of the present study was to elucidate the prevalence and risk factors for newly developed and/or exacerbated ILD, based on post-marketing surveillance data, in which all RA patients receiving LEF were pre-registered and monitored for 24 weeks in Japan. Methods: We analysed data from a cohort of 5054 RA patients who were prescribed LEF since its launch in September 2003 in Japan. Multivariable logistic analysis was performed to identify the risk factors for newly developed and/or exacerbation of ILD. Results: Sixty-one (1.2%) of 5054 RA patients who received LEF were reported to have development and/or exacerbation of ILD as an adverse drug reaction to LEF, judged by the attending physicians. Multivariable logistic regression analysis identified pre-existing ILD [odds ratio (OR) 8.17; 95% CI 4.63, 14.4], cigarette smoking (3.12; 95% CI 1.73, 5.60), a low body weight (<40 kg vs >50 kg) (2.91; 95% CI 1.15, 7.37) and the use of a loading dose (3.97; 95% CI 1.22, 12.9) as independent risk factors for LEF-induced ILD. Conclusions: Pre-existing ILD was the most important risk factor for LEF-induced ILD. We suggest that LEF should not be prescribed for RA patients complicated with ILD. © The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.

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Prediction of efficacy of anti-TNF biologic agent, infliximab, for rheumatoid arthritis patients using a comprehensive transcriptome analysis of white blood cells

竹内勤

Biochemical and Biophysical Research Communications 387 （ 2 ） 261 - 265 2009年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0006-291X

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Postmarketing surveillance of the safety and effectiveness of etanercept in Japan

Koike Takao, Harigai Masayoshi, Inokuma Shigeko, Inoue Kazuhiko, Ishiguro Naoki, Ryu Junnosuke, Takeuchi Tsutomu, Tanaka Yoshiya, Yamanaka Hisashi, Fujii Koichi, Freundlich Bruce, Suzukawa Michio

Journal of Rheumatology 36 （ 5 ） 898 - 906 2009年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

Objective. Postmarketing surveillance (PMS) was conducted evaluating safety and effectiveness of etanercept (ETN; Enbrel®) in Japan, following all patients with rheumatoid arthritis (RA) during the conditional approval period of ETN. Methods. Registration of patients from 1,334 medical sites was conducted between March 2005 and April 2007. Patients were followed for 24 weeks; data regarding patients' background, safety, and effectiveness was recorded centrally. Adverse events (AE) and adverse drug reactions (ADR) were coded using the Medical Dictionary for Regulatory Activities. Effectiveness was measured using the Disease Activity Score 28 (DAS28). Results. Of 14,369 patients registered, data collection and evaluation for 7,091 patients by March 2006 is reported. At least 1 AE was observed for 2,173 patients (30.6%); 60% of AE occurred within 8 weeks of starting ETN. Most frequent AE were injection site reaction (n = 377, 5.3%) and rash (n = 228, 3.2%). Serious AE occurred in 403 patients (5.7%); most frequent were pneumonia (n = 59, 0.8%) and interstitial lung disease (n = 42, 0.6%). Pneumonia was the most common specifically important ADR (n = 102, 1.4%). Mean baseline DAS28 was 6.0, which reduced to 4.4 within 4 weeks, and to 3.9 within 24 weeks. The proportion of patients having good or moderate EULAR response measured by DAS28 was 84.1% at Week 24. Effectiveness rates were more favorable in patients concomitantly using methotrexate. Good or moderate EULAR response rate among patients switched from infliximab was 84.9%. Conclusion. This extensive observational trial, including all patients with RA in Japan taking ETN, found ETN to be both effective and well tolerated by Japanese patients with RA. Trial registration: clinicaltrials.gov identifier NCT00503503. The Journal of Rheumatology Copyright © 2009. All rights reserved.

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Pneumocystis jiroveci pneumonia in patients with rheumatoid arthritis treated with infliximab

Komano Yukiko, Harigai Masayoshi, Koike Ryuji, Sugiyama Haruhito, Ogawa J. U N, Saito Kazuyoshi, Sekiguchi Naoya, Inoo Masayuki, Onishi Ikuko, Ohashi Hiroyuki, Amamoto Fujio, Miyata Masayuki, Ohtsubo Hideo, Hiramatsu Kazuko, Iwamoto Masahiro, Minota Seiji, Matsuoka Naoki, Kageyama Goichi, Imaizumi Kazuyoshi, Tokuda Hitoshi, Okochi Yasumi, Kudo Koichiro, Tanaka Yoshiya, Takeuchi Tsutomu, Miyasaka Nobuyuki

Arthritis Care and Research 61 （ 3 ） 305 - 312 2009年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2151-4658

Objective. To establish proper management of Pneumocystis jiroveci pneumonia (PCP) in rheumatoid arthritis (RA) patients treated with infliximab. PCP has been observed in 0.4% of patients with RA treated with infliximab in Japan. Methods. Data from patients with RA (n = 21) who were diagnosed with PCP during infliximab treatment and from 102 patients with RA who did not develop PCP during infliximab therapy were collected from 14 rheumatology referral centers in Japan. A retrospective review of these patients and a case-control study to compare patients with and without PCP were performed. Results. The median length of time from the first infliximab infusion to the development of PCP was 8.5 weeks. At the onset of PCP, the median dosages of prednisolone and methotrexate were 7.5 mg/day and 8 mg/week, respectively. Pneumocystis jiroveci was microscopically identified in only 2 patients, although the polymerase chain reaction test for the organism was positive in 20 patients. The patients with PCP had significantly lower serum albumin levels (P < 0.001) and lower serum IgG levels (P < 0.001) than the patients without PCP. Computed tomography of the chest in all patients with PCP revealed ground-glass opacity either with sharp demarcation by interlobular septa or without interlobular septal boundaries. Sixteen of the 21 patients with PCP developed acute respiratory failure, but all survived. Conclusion. PCP is a serious complication that may occur early in the course of infliximab therapy in patients with RA. For the proper clinical management of this infectious disease, physicians need to be aware of the possibility of PCP developing during infliximab therapy. © 2009, American College of Rheumatology.

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Single center prospective study of tacrolimus efficacy and safety in treatment of rheumatoid arthritis

Suzuki Katsuya, Kameda Hideto, Amano Koichi, Nagasawa Hayato, Takei Hirofumi, Sekiguchi Naoya, Nishi Eiko, Ogawa Hiroe, Tsuzaka Kensei, Takeuchi Tsutomu

Rheumatology International 29 （ 4 ） 431 - 436 2009年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0172-8172

The aim of this study was to prospectively evaluate the efficacy and safety of tacrolimus for treating rheumatoid arthritis (RA) patients in clinical practice. Fifty-five active RA patients who had been resistant or intolerant to other disease-modifying antirheumatic drugs were enrolled in this open-label trial. Patients were administered tacrolimus at a dosage of 1, 2 or 3 mg once daily, and followed up for 24 weeks. They were divided into three groups according to their dosage. Efficacy and safety were evaluated utilizing clinical and laboratory findings. Eighty percent of the patients had moderate or high disease activity; 55% were elderly and 53% had complications; 65% of the patients were started on tacrolimus as a monotherapy. Moderate or good response rates were achieved as follows: 38.2% (4 weeks); 41.8% (12 weeks); and 45.6% (24 weeks). Adverse events were observed in seven cases (12.7%). Only one case required hospitalization due to severe hyperglycemia caused by a high tacrolimus concentration (24.2 ng/ml); we suspected a drug interaction in this subject. Mean concentrations were dose-dependent in the 1, 2, and 3 mg/day groups (2.96, 4.29, and 8.32 ng/ml, respectively). Four cases of high concentration (over 10 ng/ml), without any signs or symptoms, were observed in the 3 mg/day group; in these cases, doses were decreased and no severe adverse events occurred. Tacrolimus was found to be both effective and safe in treating active RA patients with complicated backgrounds in clinical practice. Blood concentration measurements and dose adjustments should be performed to prevent severe adverse events in a 3 mg/day group. © 2009 Springer-Verlag.

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Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI)

竹内勤

Modern Rheumatology 19 （ 1 ） 12 - 19 2009年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

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A combination of biochemical markers of cartilage and bone turnover, radiographic damage and body mass index to predict the progression of joint destruction in patients with rheumatoid arthritis treated with disease-modifying anti-rheumatic drugs

Hashimoto Jun, Garnero Patrick, van der Heijde Désirée, Miyasaka Nobuyuki, Yamamoto Kazuhiko, Kawai Shinichi, Takeuchi Tsutomu, Yoshikawa Hideki, Nishimoto Norihiro

Modern Rheumatology 19 （ 3 ） 273 - 282 2009年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

The aim of this study was to evaluate the predictive value of biological, radiological and clinical parameters for the progression of radiographic joint damage in rheumatoid arthritis (RA) patients treated with conventional disease-modifying anti-rheumatic drugs (DMARDs). We analyzed the 145 patients with active RA for less than 5 years who were participating in the prospective 1-year randomized controlled trial of tocilizumab (SAMURAI trial) as a control arm treated with conventional DMARDs. Progression of joint damage was assessed by sequential radiographs read by two independent blinded X-ray readers and scored for bone erosion and joint space narrowing (JSN) using the van der Heijde-modified Sharp method. Multivariate analysis revealed that increased urinary levels of C-terminal crosslinked telopeptide of type II collagen (U-CTX-II), an increased urinary total pyridinoline/total deoxypyridinoline (U-PYD/DPD) ratio and low body mass index (BMI) at baseline were independently associated with a higher risk for progression of bone erosion. In addition to these three variables, the JSN score at baseline was also significantly associated with an increased risk of progression of the JSN score and total Sharp score. High baseline U-CTX-II levels, U-PYD/DPD ratio and JSN score and a low BMI are independent predictive markers for the radiographically evident joint damage in patients with RA treated with conventional DMARDs. © Japan College of Rheumatology 2009.

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Improvement of the HAQ score by infliximab treatment in patients with RA

Nagasawa Hayato, Kameda Hideto, Sekiguchi Naoya, Amano Kouichi, Takeuchi Tsutomu

Modern Rheumatology 19 （ 2 ） 166 - 172 2009年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

We conducted a two-year prospective study to clarify the efficacy of infliximab at improving the health assessment questionnaire (HAQ) score and associated factors in 67 patients with advanced rheumatoid arthritis (RA). All patients were scheduled to receive infliximab at a dose of 3 mg/kg at weeks 0, 2, 6 and every eight weeks thereafter through to week 102, and were fully examined at the time of each infusion. Parameters of disease activity such as the serum level of C-reactive protein (CRP), the serum level of matrix metalloproteinase-3 (MMP-3) and the 28-joint disease activity score (DAS28) were obtained, and the functional capabilities of the patients were assessed using the HAQ score. The serum CRP, the MMP-3, the DAS28(CRP) level, and the mean HAQ score decreased rapidly at two weeks after the start of infliximab treatment (CRP from 3.7 to 0.9 mg/dl, MMP-3 from 362.3 to 192.8 ng/ml, DAS28(CRP) from 5.6 to 3.7, and HAQ score from 1.5 to 0.9). Compared with the baseline values, the mean progression of the modified van der Heijde (vdH) - Sharp score after one year was 4.4 ± 5.8 (median: 3.0), and that after two years was 3.1 ± 6.9 (median: 1.0). A 93% reduction in the rate of joint destruction, as measured using the vdH-Sharp score, was estimated after infliximab therapy. Patients with less joint damage (shorter disease duration or lower vdH-Sharp score) regained more of their daily activities. The present study demonstrated the importance of activity control before the progression of irreversible factors, such as joint destruction, for maintaining the functional capacities of RA patients. © Japan College of Rheumatology 2008.

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Notable difference between the development of vertebral fracture and osteonecrosis of the femoral head in patients treated with high-dose glucocorticoids for systemic rheumatic diseases

Kameda Hideto, Amano Koichi, Nagasawa Hayato, Ogawa Hiroe, Sekiguchi Naoya, Takei Hirofumi, Suzuki Katsuya, Takeuchi Tsutomu

Internal Medicine 48 （ 22 ） 1931 - 1938 2009年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0918-2918

Objective: Vertebral fracture (VF) and osteonecrosis of the femoral head (OFH) are serious concerns in patients with rheumatic diseases treated with high-dose glucocorticoids (GCs). We comparatively examined the risk factors of VF and OFH in patients who had recently received high-dose GC therapy. Patients and Methods: Patients with rheumatic diseases receiving GCs (≥0.5 mg/kg/day for prednisolone equivalent) within the past 2 months were enrolled in this study, and treated with 200 mg/day of etidronate cyclically. The bone mineral density (BMD) of the lumbar spine (L2-4) was examined by QDR2000. OFH was evaluated by magnetic resonance imaging (MRI). [ClinicalTrials.gov identifier: NCT00679978]. Results: Forty-four patients completed the 2-year study including annual X-rays and the BMD analysis. MRI evaluation at entry and 2 years was performed in 41 patients. The BMD values with anteroposterior (AP) and lateral views decreased by 6.4% and 9.7%, respectively, in the first year, but were stable in the second year. Eleven patients developed VF and 9 patients developed OFH. The risk factors for VF included previous VF and a low BMD value (T score<-1.5) of AP view at baseline with an odds ratio (OR) of 14.9 (95% CI 2.9-76.4), while the risk factor for OFH was a recent maximum GC dosage (>1.2 mg/kg/day versus≤; OR=7.7, 95%CI 1.3-45.5) and a decrease in BMD value of lateral view (>15% versus≤ OR=6.7, 95% CI 1.2-36.1) in the first year. Conclusion: The development of VF relies on the predisposing factors, while that of OFH depends on the response to high-dose GC therapy. © 2009 The Japanese Society of Internal Medicine.

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Impact of trough serum level on radiographic and clinical response to infliximab plus methotrexate in patients with rheumatoid arthritis

Takeuchi Tsutomu, Miyasaka Nobuyuki, Inoue Kazuhiko, Abe Tohru, Koike Takao

Modern Rheumatology 19 （ 5 ） 478 - 487 2009年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

This study is a prospective, randomized, double-blind study to compare the efficacy and safety of 10 mg/kg infliximab with those of 3 mg/kg infliximab treatment in methotrexate-refractory rheumatoid arthritis patients. After the patients received 3 mg/kg infliximab infusion at weeks 0, 2, and 6, they were randomly assigned to be administered 3, 6 or 10 mg/kg infliximab every 8 weeks from week 14 to 46. Mean American College of Rheumatology improvement (ACR-N) at week 54, the primary endpoint, was 51.3% and 58.3% for the 3 mg/kg and 10 mg/kg groups, respectively, with a statistically significant difference. Treatment with 10 mg/kg was found to be remarkably beneficial in patients who had not responded to three infusions with 3 mg/kg at week 10. The median changes in the modified Sharp score were 0.0 in the two groups. There were no significant differences in the incidences of adverse events between the groups. In patients who achieved better clinical response or greater inhibition of progression of joint damage, trough serum infliximab level was significantly higher than in patients who did not. The magnitudes of both efficacies were correlated with the trough serum infliximab level (ClinicalTrials.gov number: NCT00691028). © Japan College of Rheumatology 2009.

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Severe acute thrombotic exacerbation in two cases with anti-phospholipid syndrome after retreatment with rituximab in phase I/II clinical trial for refractory systemic lupus erythematosus

Suzuki K., Nagasawa H., Kameda H., Amano K., Kondo T., Itoyama S., Tanaka Y., Takeuchi T.

Rheumatology 48 （ 2 ） 198 - 199 2009年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1462-0324

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Effect of interleukin-2 on synthesis of B cell activating factor belonging to the tumor necrosis factor family (BAFF) in human peripheral blood mononuclear cells

竹内勤

Cytokine 44 （ 1 ） 44 - 48 2008年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1043-4666

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Tacrolimus has pleiotropic morelecular effects on human regulatory T cells

竹内勤

Arthritis and Rheumatism 58 （ 9 ） S839 - S839 2008年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0004-3591

Altered distribution of aquaporin 5 and its C-terminal binding protein in the lacrimal glands of a mouse model for Sjögren's syndrome

Ohashi Yoshiki, Tsuzaka Kensei, Takeuchi Tsutomu, Sasaki Yasumasa, Tsubota Kazuo

Current Eye Research 33 （ 8 ） 621 - 629 2008年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0271-3683

Purpose: To investigate the distribution and expression of aquaporin 5 (AQP5) and its C-terminal binding protein in the apical membrane of the lacrimal glands (LGs) in a mouse model for Sjogren's syndrome (SS). Methods: The LGs of NOD mice (mouse model for SS) and ICR mice (normal control) were homogenized and delivered into the affinity columns bound to synthetic AQP5 C-terminal peptide. The eluates were analyzed by electrophoresis and liquid chromatography mass spectrometry/mass spectrometry (LC-MS/MS) techniques.Results: AQP5 from the NOD mice exhibited the capacity to bind a 21-kDa protein that was lacking in the ICR mice. Instead, ICR mouse expressed a 17-kDa AQP5 binding protein that was absent in LGs of SS. LC-MS/MS analysis revealed these respective proteins to be major urinary protein 4 (MUP4) and prolactin-inducible protein (PIP). The treatment of ICR mice with antisense PIP oligonucleotides decreased immunostaining of AQP5 in the apical membrane. Conclusions: These observations suggest that the binding of PIP to the C-terminal portion of AQP5 may cause AQP5 to be transported to the apical membrane of LGs. Correction of the aberrant binding of PIP to the AQP5 C-terminus could normalize AQP5 trafficking to the apical membrane, leading to a treatment for patients with SS. Copyright © Informa Healthcare USA, Inc.

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Messenger ribonucleic acid expression profile in peripheral blood cells from RA patients following treatment with an anti-TNF-α monoclonal antibody, infliximab

Sekiguchi N., Kawauchi S., Furuya T., Inaba N., Matsuda K., Ando S., Ogasawara M., Aburatani H., Kameda H., Amano K., Abe T., Ito S., Takeuchi T.

Rheumatology 47 （ 6 ） 780 - 788 2008年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1462-0324

Objectives. We monitored the mRNA expression profiles of peripheral blood cells during treatment with a TNF-α inhibitor, infliximab, in patients with RA. Using a DNA microarray analysis, we demonstrated a unique set of genes, with distinct baseline and post-treatment changes in expression between responders and non-responders to infliximab treatment. Methods. Using a customized low-density cDNA microarray with 747 genes and a reliable data collection system, we monitored the mRNA expression profiles of whole blood cells from 18 RA patients before and after the infusion of infliximab for up to 22 weeks. The clinical response to treatment with infliximab was determined using the ACR response criteria, the disease activity score of 28 joints (DAS28), and individual clinical parameters. The patients were classified as responders or non-responders based on their ACR50% response at 22 weeks. Results. Approximately 15% of the total genes were found to exhibit a >1.5-fold change, compared with their reference values, at one or more time points during the 22 weeks of infliximab therapy. The expression of inflammatory genes, such as IFN-related genes, was strongly correlated with the serum level of CRP and the DAS28. The increased expression of inflammatory genes in responders was normalized within 2 weeks and then remained at a normal level during the treatment period. In contrast, in the non-responders, the elevated expression at baseline, although it was significantly decreased at 2 weeks, returned to the baseline level after 14 weeks. In addition to inflammatory genes, we identified several groups of genes with distinct differences in expression between the responders and non-responders. Conclusions. Our results suggest that a customized low-density microarray is useful for monitoring mRNA expression profiles in peripheral blood cells, enabling us to identify a unique set of genes with differentially regulated expressions in responders and non-responders to a TNF inhibitor among patients with RA. © The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.

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Severe degenerative change of multiple organs mediated by chronic active Epstein-Barr virus infection with infected T-cell expansion

Tokuhira Michihide, Iizuka Atsushi, Watanabe Reiko, Sekiguchi Naoya, Sato Norihide, Chien Chen Kang, Sekiguchi Yasunobu, Nemoto Tomoe, Hanzawa Kyoko, Tamaru Jun Ichi, Itoyama Shinji, Suzuki Hiroshi, Takeuchi Tsutomu, Mori Shigehisa, Kizaki Masahiro

International Journal of Hematology 87 （ 5 ） 520 - 526 2008年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0925-5710

We here report the case of a young Japanese woman diagnosed with chronic active Epstein-Barr virus (EBV) infection. Intensive therapy with the CHOP regimen was partially able to control virus expansion, but various central nervous system symptoms appeared and gradually progressed. EBV-encoded RNA, detected using in situ hybridization, disclosed the presence of EBV in liver and bone marrow tissue, and real-time PCR revealed the presence of EBV in the cerebrospinal fluid (CSF) and serum. CD3+CD4+CD8-CD56- T-cell expansion in the peripheral blood (PB) and CSF was also observed. Atrophic brain changes were progressive, and the patient died of central nervous system disturbance and pulmonary hemorrhage a year after diagnosis. Autopsy revealed that EBV-infected T lymphocytes with a phenotype similar to those seen in PB and CSF had infiltrated multiple organs: the lymph nodes, bone marrow, endocardium, pericardium, myocardium, spleen, liver, and spinal cord. There have been few previous reports of severe degenerative changes in the myocardium, liver, and spinal cord in patients with EBV infection. Although EBV occasionally infiltrates the central nervous system and brain, atrophic changes mediated by EBV are rare. The autopsy results of this case suggest the possibility of EBV-mediated, severe degenerative changes in multiple organs. © 2008 The Japanese Society of Hematology.

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Retrospective clinical study on the notable efficacy and related factors of infliximab therapy in a rheumatoid arthritis management group in Japan

Tanaka Yoshiya, Takeuchi Tsutomu, Inoue Eisuke, Saito Kazuyoshi, Sekiguchi Naoya, Sato Eri, Nawata Masao, Kameda Hideto, Iwata Shigeru, Amano Kouichi, Yamanaka Hisashi

Modern Rheumatology 18 （ 2 ） 146 - 152 2008年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Biologics targeting TNF have brought about a paradigm shift in the treatment of rheumatoid arthritis (RA) and infliximab, anti-TNF-α chimeric monoclonal antibody, was marketed in 2003 in Japan. We previously reported on the RECONFIRM study, a retrospective clinical study on the efficacy of infliximab therapy in a RA management group in Japan, where we evaluated the clinical response after 22 weeks of the therapy in 258 patients. The study reported here was aimed at reconfirming the clinical efficacy of the infliximab therapy and demographic factors related to the efficacy over a 54-week study period in 410 RA patients in the same study group. Infliximab was infused according to the domestically approved method, and the clinical response was evaluated following 54 weeks of infliximab therapy using the European League Against Rheumatism (EULAR) response criteria. Disease activity was assessed by DAS28-CRP (Disease Activity Score including a 28-joint count/C-reactive protein). Infliximab was discontinued in 24.4% of the 410 patients at 54 weeks and 9.3% and 8.1% discontinued the therapy due to adverse events and inefficiency, respectively. Average DAS28-CRP decreased from 5.5 at week 0 to 3.1 at week 54 after the therapy. Patients in remission and those showing low-, moderate-, and high-disease activity changed from 0.0, 1.0, 9.0 and 90.0%, respectively, at the start of the study to 27.6, 11.7, 34.4 and 26.3%, respectively, at week 54. Younger age, RF-negativity and low scores of DAS28-CRP showed significant correlations with remission at week 54. EULAR response criteria - good, moderate, and no response to infliximab - were 37.0, 41.7 and 21.2%, respectively. In conclusion, we reconfirmed the clinical efficacy of infliximab and demographic factors related to the efficacy over a 54-week study period in 410 Japanese patients with RA using DAS28-CRP and EULAR response criteria. © Japan College of Rheumatology 2008.

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Molecular effects to human regulatory T cells by treatment with T cell activation inhibitor and TNF blockade

竹内勤

FASEB Journal 22 S626 - S627 2008年04月

研究論文（国際会議プロシーディングス）, 共著, 査読有り, ISSN 0892-6638

Conservative sequences in 3′UTR of TCRζ mRNA regulate TCRζ in SLE T cells

Tsuzaka Kensei, Itami Yuka, Kumazawa Chika, Suzuki Miyuki, Setoyama Yumiko, Yoshimoto Keiko, Suzuki Katsuya, Abe Tohru, Takeuchi Tsutomu

Biochemical and Biophysical Research Communications 367 （ 2 ） 311 - 317 2008年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0006-291X

We have demonstrated that T-cell receptor ζ (ζ) mRNA with a 562-bp deleted alternatively spliced 3′-untranslated region (3′UTR) observed in T cells of patients with systemic lupus erythematosus (SLE) can lead to a reduction in ζ and TCR/CD3 (J. Immunol., 2003 & 2005). To determine the region in ζ mRNA 3′UTR for the regulation of ζ, ζ mRNA with 3′UTR truncations ligated into pDON-AI was used to infect murine T-cell hybridoma MA5.8 cells, which do not contain ζ. As a Western blot analysis demonstrated the importance of the regions from +871 to +950, containing conservative sequence 1 (CS1), and +1070 to +1136, containing CS2, for the production of ζ, we constructed MA5.8 mutants carrying ζ mRNA 3′UTR with deletions of these regions (ΔCS1 and ΔCS2 mutants). Western blot and FACS analyses showed significant reduction in the cell surface ζ and TCR/CD3 in both these mutants, and IL-2 production was decreased, compared with MA5.8 cells transfected with wild-type ζ mRNA. Furthermore, real-time PCR demonstrated the instability of ζ mRNA with 3′UTR deletions in these MA5.8 mutants. In conclusion, CS1 and CS2 may be responsible for the regulation of ζ and TCR/CD3 through the stability of ζ mRNA in SLE T cells. © 2007 Elsevier Inc. All rights reserved.

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Postmarketing surveillance of the safety profile of infliximab in 5000 Japanese patients with rheumatoid arthritis

Takeuchi Tsutomu, Tatsuki Y., Nogami Y., Ishiguro N., Tanaka Y., Yamanaka H., Kamatani N., Harigai M., Ryu J., Inoue K., Kondo H., Inokuma S., Ochi T., Koike T.

Annals of the Rheumatic Diseases 67 （ 2 ） 189 - 194 2008年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

Objectives: A large-scale postmarketing surveillance (PMS) study was carried out to determine the safety profile of infliximab in Japanese patients with rheumatoid arthritis (RA). Methods: The PMS study was performed for all patients with RA who were treated with infliximab. They were consecutively registered in the PMS study at the initiation of infliximab treatment and were prospectively monitored with all adverse events noted for a period of 6 months. All case reports, which include safety-related events, were collected monthly. Results: Adverse drug reactions (ADRs) were assessed for 6 months in 5000 patients who were consecutively enrolled in the PMS study. The incidence rates of total and serious ADRs were 28.0% and 6.2%, respectively. "Infections" or "respiratory disorders" were most commonly observed among serious ADRs. Bacterial pneumonia developed in 2.2%, tuberculosis in 0.3%, suspected Pneumocystis jiroveci pneumonia (PCP) in 0.4% and interstitial pneumonitis in 0.5%. Bacterial pneumonia (for which individuals of male gender, of older age and those with advanced rheumatoid arthritis and comorbid respiratory disease were most at risk) began to develop immediately after the start of treatment, while tuberculosis, PCP and interstitial pneumonitis developed about 1 month later. Serious infusion reactions were observed in 0.5% and were more likely to occur in patients who had participated in previous clinical trials of infliximab. Conclusion: This postmarketing surveillance study of patients treated with infliximab showed that infliximab in combination with low-dose MTX was well tolerated in Japanese patients with active RA.

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Interaction of KLRG1 with E-cadherin

Rosshart Stephan, Hofmann Maike, Schweier Oliver, Pfaff Anne Kathrin, Yoshimoto Keiko, Takeuchi Tsutomu, Molnar Eszter, Schamel Wolfgang W., Pircher Hanspeter

European Journal of Immunology 38 （ 12 ） 3354 - 3364 2008年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0014-2980

The killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor expressed by memory T cells and NK cells in man and mice. It is frequently used as a cell differentiation marker and members of the cadherin family are ligands for KLRG1. The present study provides new insights into the interaction of mouse KLRG1 with E-cadherin. Firstly, we demonstrate that co-engagement of KLRG1 and CD3/TCR in a spatially linked manner was required for inhibition arguing against the notion that KLRG1-ligation per se transmits inhibitory signals. Secondly, experiments with T cells carrying Y₇F-mutant KLRG1 molecules with a replacement of the tyrosine residue to phenylalanine in the single ITIM indicated that the inhibitory activity of KLRG1 is counteracted to some degree by increased interaction of KLRG1⁺ T cells with E-cadherin expressing target cells. Thirdly, we demonstrate that deletion of the first or the second external domain of E-cadherin abolished reactivity in KLRG1-reporter cell assays. Finally, we made the intriguing observation that KLRG1 formed multimeric protein complexes in T cells in addition to the previously described mono- and dimeric molecules. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA.

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Retrospective clinical study on the notable efficacy and related factors of infliximab therapy in a rheumatoid arthritis management group in Japan

Takeuchi Tsutomu, Yamanaka Hisashi, Inoue Eisuke, Nagasawa Hayato, Nawata Masao, Ikari Katsunori, Saito Kazuyoshi, Sekiguchi Naoya, Sato Eri, Kameda Hideto, Iwata Shigeru, Mochizuki Takeshi, Amano Kouichi, Tanaka Yoshiya

Modern Rheumatology 18 （ 5 ） 447 - 454 2008年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

The anti-TNF-α chimeric monoclonal antibody infliximab is the first biologic to be approved for rheumatoid arthritis (RA) in Japan, and post-marketing surveillance of all of the Japanese cases treated with infliximab has been conducted to explore the safety of infliximab therapy. In addition, a retrospective clinical study on the notable efficacy and related factors of infliximab therapy in an RA management group in Japan (RECONFIRM and RECONFIRM-2) has demonstrated clinical responses. However, information on the effect of infliximab on joint destruction in Japanese RA patients remains insufficient. In this study, we retrospectively analyzed X-ray data from 67 patients in whom both hand and foot X-rays at baseline and at 54 weeks had been available among the 410 cases in the RECONFIRM-2 study. By scoring the X-rays according to the modified van der Heijde (vdH)-Sharp method, we found that the total vdH-Sharp score in the RA patients before infliximab therapy was 104.40 ± 87.34 and the yearly progression was 21.33, indicating relatively rapid progression. After infliximab therapy for 54 weeks, the total vdH-Sharp score at 54 weeks was 104.37 ± 86.87 and the estimated yearly progression was -0.03, indicating the almost complete inhibition of progression. The RECONFIRM-2J study confirmed the significant ability of infliximab to halt joint destruction in Japanese RA patients, and showed that joint destruction was significantly associated with disease activity and the dose of MTX in the patients with moderate and advanced disease durations, respectively, before infliximab therapy. © Japan College of Rheumatology 2008.

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Proposals for leflunomide use to avoid lung injury in patients with rheumatoid arthritis

Inokuma Shigeko, Sato Takeo, Sagawa Akira, Matsuda Takemasa, Takemura Tamiko, Ohtsuka Takeshi, Saeki Yukihiko, Takeuchi Tsutomu, Sawada Tetsuji

Modern Rheumatology 18 （ 5 ） 442 - 446 2008年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Among the 5,043 consecutive patients registered in the postmarketing surveillance for leflunomide, 61 were reported to have lung injury and 24 died from it. The adjusted multivariate logistic regression analysis of the risk factors showed that preexisting interstitial lung disease posed the greatest risk, as well as loading dose, smoking history, and low body weight of 40 kg or less with odds ratios of 8.17, 3.97, 3.12, and 2.91, respectively. In 12 patients, lung injury developed even 2 months after leflunomide withdrawal. When patients with (n = 9) and without (n = 13) fatal outcome were compared, eight out of the former, and six out of the latter had preexisting interstitial lung disease; the former showed severe hypoxemia, high serum C-reactive protein level, hypoalbuminemia, and continuous lymphocytopenia, and required mechanical ventilation. On the basis of these results and literature review, the committee proposes that leflunomide should only be recommended as a second-line drug, should not be administered to patients with preexisting interstitial lung disease, should also not be administered to patients with smoking history or those with low body weight, and should be administered without loading dose. Careful monitoring is necessary, and when lung injury develops, leflunomide elimination using colestyramine is mandatory. © Japan College of Rheumatology 2008.

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Clinical and radiological features of Pneumocystis pneumonia in patients with rheumatoid arthritis, in comparison with methotrexate pneumonitis and Pneumocystis pneumonia in acquired immunodeficiency syndrome: A multicenter study

竹内勤

Internal Medicine 47 （ 10 ） 915 - 923 2008年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0918-2918

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Update on the Japanese guidelines for the use of infliximab and etanercept in rheumatoid arthritis

Koike Ryuji, Takeuchi Tsutomu, Eguchi Katsumi, Miyasaka Nobuyuki

Modern Rheumatology 17 （ 6 ） 451 - 458 2007年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Application of biological agents targeting tumor necrosis factor-α (TNF-α) caused a paradigm shift in the treatment of rheumatoid arthritis (RA). The introduction of infliximab in 2003 and etanercept in 2005 in Japan had a significant impact on both Japanese rheumatologists and RA patients, although serious adverse effects such as bacterial pneumonia, tuberculosis and Pneumocystis jiroveci pneumonia are significant concerns. Based on the data from post-marketing surveillance in Japan and accumulating evidence worldwide, the Internal Medicine Rheumatology Study Group of the Ministry of Health, Labor and Welfare (MHLW), Japan, has updated the guidelines for the use of anti-TNF-α agents for RA, which were subsequently approved by the Board of Japan College of Rheumatology (JCR). In the present revised guidelines, we combined the guidelines for use of each of infliximab and etanercept together with some modifications and precautions, paying special attention to serious adverse reactions. Although it is still controversial whether the use of TNF-α blocking agents per se increases the risk of infection or not, bacterial pneumonia, regardless of the pathogens, is the most frequent complications in RA. The risk factors associated with pneumonia identified in the post-marketing surveillance of infliximab in Japan are presented in this guideline. The diagnostic algorithm is also designed for early diagnosis and treatment of pulmonary lesions seen during the treatment of biological agents. Preventive measures and precautions against tuberculosis, another frequent and significant complication in Japan, are also described. Furthermore, risk factors for developing Pneumocystis pneumonia, which uniquely occurs at 30- to 50-fold frequency under TNF-α blockade therapy in Japan, are described here and its preventive measures are discussed. It is stressed that secondary-care rheumatologists should be better familiarized with the proper use of TNF-α blocking agents and be alert to any adverse events for a better management of RA patients. © Japan College of Rheumatology 2007.

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Clinical significance of elevated serum levels of matrix metalloproteinase-3 and C-reactive protein in patients with rheumatoid arthritis

Nagasawa Hayato, Kameda Hideto, Amano Koichi, Takeuchi Tsutomu

APLAR Journal of Rheumatology 10 （ 4 ） 295 - 299 2007年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0219-0494

Aim: Serum levels of C-reactive protein (CRP) and matrix metalloproteinase-3 (MMP-3) are used as indicators of the activity of rheumatoid arthritis (RA). The aim of this study was to characterize the clinical features of patients showing exclusive elevation of either serum CRP or MMP-3, and the differences in the time-course of changes between the serum levels of MMP-3 and CRP after initiation of therapy. Methods: A total of 129 RA patients were classified into four groups according to the serum levels of CRP and MMP-3 at the time of enrolment: Negative for both CRP and MMP-3 levels; positive for both; positive for CRP alone (CRP-positive group); and positive for MMP-3 alone (MMP-3-positive group). The analysis included evaluation of the serum CRP and MMP-3 levels, and the Lansbury Articular Index at enrolment and at final observation. Results: In the CRP-positive group (19%), 21% of the patients remained CRP-positive at the final observation; 42% became double-negative, and 31% became double-positive. In contrast, in the MMP-3-positive group (9%), about two-thirds of the patients remained MMP-3-positive at the final observation. The disease duration in the MMP-3-positive group was significantly longer, and the ratio of the number of large swollen joints to the total number of swollen joints was higher as compared with that in the other groups. Furthermore, elevated serum CRP responded faster to disease-modifying antirheumatic drug therapy than elevated serum MMP-3. Conclusions: Serum CRP is a better predictor of the response to treatment than serum MMP-3, which is associated to a greater extent with large joint involvement. © 2007 Asia Pacific League of Associations for Rheumatology.

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Down-regulation of Fas-ligand mRNA in Sjögren's syndrome patients with enlarged exocrine glands

Tsuzaka Kensei, Matsumoto Yukihiro, Sasaki Yasumasa, Abe Tohru, Tsubota Kazuo, Takeuchi Tsutomu

Autoimmunity 40 （ 7 ） 497 - 502 2007年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0891-6934

We have reported that Sjögren's syndrome (SS) patients with enlarged exocrine glands (EEG) formerly referred to as Mikulicz's disease were defective with Fas-ligand (FasL) expression in PBL and lacrimal glands (LGs). To investigate the mechanisms of reduced FasL expression in SS patients with EEG, FasL mRNA expression level was determined using real-time PCR. The FasL gene promoter region (from -1197 to -3) was also amplified using PCR and specific primers. Expression of the FasL mRNA in the LGs and PBLs of three SS patients with EEG was significantly decreased. Direct sequencing revealed a heterozygous point mutation (-259T/C) in the FasL gene promoter region in one SS patient with EEG. A luminescent β-galactosidase (β-gal) reporter assay using a pβgal Enhancer Vector demonstrated that β-gal activity from the vector including the mutant (-259C) FasL (pβgal/mFasL) gene promoter region (735±42) was similar (p = 0.13) to that from a pβgal Enhancer Vector without the gene promoter region (603±66). On the other hand, the β-gal activity was significantly lower (p<0.0001) than that from a vector including the wild-type (-259T) FasL (pbeta;gal/wFasL) (3226±148). In conclusion, the down-regulation of FasL in SS patients with EEG may be due to transcriptional regulation, and the point mutation at -259T/C in the FasL gene promoter region may lead to the down-regulation of FasL mRNA expression and the lymphoproliferative process observed in SS patients with EEG.

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Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI)

Nishimoto Norihiro, Hashimoto Jun, Miyasaka Nobuyuki, Yamamoto Kazuhiko, Kawai Shinichi, Takeuchi Tsutomu, Murata Norikazu, Van Heijde Desiree Der, Kishimoto Tadamitsu

Annals of the Rheumatic Diseases 66 （ 9 ） 1162 - 1167 2007年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-4967

Objective: To evaluate the ability of tocilizumab (a humanised anti-IL-6 receptor antibody) monotherapy to inhibit progression of structural joint damage in patients with RA. Methods: In a multi-centre, x ray reader-blinded, randomised, controlled trial, 306 patients with active RA of <5 years' duration were allocated to receive either tocilizumab monotherapy at 8 mg/kg intravenously every 4 weeks or conventional disease-modifying antirheumatic drugs (DMARDs) for 52 weeks. Radiographs of hands and forefeet were scored by the van der Heijde modified Sharp method. Results: Patients had a mean disease duration of 2.3 years and a disease activity score in 28 joints of 6.5 at baseline. Mean total modified Sharp score (TSS) was 29.4, which was very high despite the relatively short disease duration. At week 52, the tocilizumab group showed statistically significantly less radiographic change in TSS (mean 2.3; 95% CI 1.5 to 3.2) than the DMARD group (mean 6.1; 95% CI 4.2 to 8.0; p<0.01). Tocilizumab monotherapy also improved signs and symptoms. The overall incidences of AEs were 89% and 82% (serious AEs: 18% and 13%; serious infections: 7.6% and 4.1%) in the tocilizumab and DMARD groups, respectively. Conclusion: Tocilizumab monotherapy was generally well tolerated and provided radiographic benefit in patients with RA.

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The importance of biochemical markers of bone and cartilage turnover as the predictors of radiographic progression in patients with early rheumatoid arthritis

竹内勤

Journal of Bone and Mineral Resaerch 22 S472 - S472 2007年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0884-0431

Lymphomatoid granulomatosis and diffuse alveolar damage associated with methotrexate therapy in a patient with rheumatoid arthritis

竹内勤

Clinical Rheumatology 26 （ 9 ） 1585 - 1589 2007年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0770-3198

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A multicenter phase I/II trial of rituximab for refractory systemic lupus erythematosus

Tanaka Yoshiya, Yamamoto Kazuhiko, Takeuchi Tsutomu, Nishimoto Norihiro, Miyasaka Nobuyuki, Sumida Takayuki, Shima Yoshihito, Takada Kazuki, Matsumoto Isao, Saito Kazuyoshi, Koike Takao

Modern Rheumatology 17 （ 3 ） 191 - 197 2007年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Although corticosteroids and immunosuppressants are widely used for the treatments of systemic lupus erythematosus (SLE), safer and more effective therapies are prerequisite. We and others have reported that anti-CD20 antibody rituximab targeting B cells are effective for refractory SLE and, therefore, safety and clinical efficacy of rituximab in SLE was evaluated by a multicenter phase I/II clinical trial. An open-label, multicenter study of 15 patients with active and refractory SLE (total British Isles Lupus Assessment Group [BILAG] score 8 to 17) was conducted. Rituximab was administered to 5 SLE patients as 4 infusions of 500 mg/body every week and to 10 SLE patients as 2 infusions of 1000 mg/body every other week. Assessment of safety, infusion reactions and adverse effects was used as the primary outcome for clinical tolerability and was evaluated by 28 weeks. Rituximab was well tolerated, with most experiencing no significant adverse effects. B cells rapidly reduced in all patients and remained low until 6 months post-treatment. Four patients developed human antichimeric antibodies without affecting efficacy of rituximab. Changes in routine safety laboratory tests clearly related to rituximab were not observed. Nine among 14 evaluable patients achieved the major or partial clinical response of BILAG score and prednisolone dose significantly decreased at the 28 weeks. Rituximab therapy appears to be safe for the treatment of active SLE patients and holds significant therapeutic promise, at least for the majority of patients experiencing profound B-cell depletion. © Japan College of Rheumatology 2007.

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Prospective study of low-dose cyclosporine A in patients with refractory lupus nephritis

Ogawa Hiroe, Kameda Hideto, Nagasawa Hayato, Sekiguchi Naoya, Takei Hirofumi, Tsuzaka Kensei, Amano Koichi, Takeuchi Tsutomu

Modern Rheumatology 17 （ 2 ） 92 - 97 2007年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

We evaluated the efficacy and safety of low-dose cyclosporine A (CsA) in patients with refractory lupus nephritis. Nine patients with systemic lupus erythematosus who had lupus nephritis resistant to previous treatment with glucocorticoids and immunosuppressants other than CsA were enrolled in a prospective, open-label study. All patients initially received 2.5 mg/kg per day of CsA; the dosage was adjusted to reach a blood trough level of 80-150ng/ml. The urinary protein concentration decreased significantly 2 weeks after the initiation of treatment. After 30 weeks of CsA treatment, the mean urinary protein concentration was more than 50% lower than the baseline value, and urinary casts had decreased significantly. There were no significant changes in the levels of serum creatinine, serum anti-double-stranded DNA antibodies, or CH50 during any part of the study. The dose of glucocorticoids was significantly tapered by approximately 50%, without any disease flare. Hypertension developed in one patient, but was controlled with antihypertensive agents. Our results suggest that low-dose CsA therapy is an effective and less toxic alternative to conventional cyclophosphamide therapy for the management of refractory lupus nephritis. © Japan College of Rheumatology 2007.

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Lymphoproliferative disorders in rheumatoid arthritis

Hoshida Yoshihiko, Xu Jing Xian, Fujita Shigeki, Nakamichi Itsuko, Ikeda Jun Ichiro, Tomita Yasuhiko, Nakatsuka Shin Ichi, Tamaru Jun Ichi, Iizuka Atsushi, Takeuchi Tsutomu, Aozasa Katsuyuki

Journal of Rheumatology 34 （ 2 ） 322 - 331 2007年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

Objective. Individuals with rheumatoid arthritis (RA) with or without methotrexate (MTX) medication occasionally develop lymphoproliferative disorders (MTX-LPD and non-MTX-LPD, respectively). The hyperimmune state of RA itself or the immunosuppressive state induced by MTX administration might contribute to development of LPD. Our objective was to characterize MTX-LPD in comparison to non-MTX-LPD and sporadic LPD in patients with RA. Methods. We compared MTX-LPD to non-MTX-LPD and sporadic LPD by evaluating 48 cases of MTX-LPD, 28 non-MTX-LPD, and 150 sporadic LPD. Results. Later onset age of LPD and female predominance were evident in patients with RA-LPD compared to sporadic LPD. The interval between the diagnosis of RA and LPD in MTX-LPD (median 132 mo) was significantly shorter than that in non-MTX-LPD (240 mo). The frequency of diffuse large B cell lymphoma (DLBCL) and positive rate of Epstein-Barr virus (EBV) in RA-LPD was significantly higher than in sporadic LPD (57.9% vs 42.7%, 27.6% vs 9.9%, respectively). After withdrawal of MTX, 11 of the MTX-LPD cases showed a spontaneous regression of tumors. The 5-year survival rate in RA-LPD (59.2%) was significantly worse than that in sporadic LPD (74.6%). Conclusion. The majority of cases of RA-LPD show similar clinicopathological characteristics irrespective of MTX medication, except for spontaneous regression of LPD after withdrawal of MTX in MTX-LPD. and a shorter interval between the diagnosis of RA and LPD in MTX-LPD than in non-MTX-LPD. RA-LPD cases showed younger age of onset, female predominance, unfavorable prognosis, and higher frequencies of DLBCL and EBV positivity compared to sporadic LPD.

De novo CD5+ diffuse large B cell lymphoma with basophilia in the peripheral blood

Tokuhira Michihide, Watanabe Reiko, Iizuka Atsushi, Sekiguchi Yasunobu, Nemoto Tomoe, Hanzawa Kyoto, Takamatsu Ichiro, Maruyama Taro, Tamaru Jun Ichi, Itoyama Shinji, Suzuki Hiroshi, Takeuchi Tsutomu, Mori Shigehisa

American Journal of Hematology 82 （ 2 ） 162 - 167 2007年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0361-8609

Basophils play an important role in allergic inflammation and are pathologically related to hematological disturbances, such as iron deficiency anemia and myeloproliferative disorders; however, they are only rarely encountered in lymphoid malignancies. Here, we report the case of a 33-year-old man with a bulky mass of the small intestine, multiple paraaortic lymphoadenopathy, pleural effusion, and ascites, who was diagnosed as a case of de novo CD5+ diffuse large B cell lymphoma (DLBCL). This patient showed a marked elevation of the basophil count in the peripheral blood, which appeared to run in parallel with the tumor burden. High dose chemotherapy followed by autologous peripheral blood cell transplantation yielded complete remission, and the patient has remained disease free for 5 years. To the best of our knowledge, this is the first report of a case of de novo CD5+ DLBCL showing marked elevation of the PB basophil count. © 2006 Wiley-Liss, Inc.

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Retrospective clinical study on the notable efficacy and related factors of infliximab therapy in a rheumatoid arthritis management group in Japan (RECONFIRM)

Yamanaka Hisashi, Tanaka Yoshiya, Sekiguchi Naoya, Inoue Eisuke, Saito Kazuyoshi, Kameda Hideto, Iikuni Noriko, Nawata Masao, Amano Kouichi, Shinozaki Mikiko, Takeuchi Tsutomu

Modern Rheumatology 17 （ 1 ） 28 - 32 2007年02月

研究論文（学術雑誌）, 査読有り, ISSN 1439-7595

This study aims to reconfirm the clinical efficacy and related factors of infliximab therapy, the first biological agent introduced to Japanese patients with rheumatoid arthritis (RA). Data of 351 RA patients with infliximab were collected retrospectively from three major centers for management of rheumatic diseases in Japan. Infliximab was infused according to the approved method, and the clinical response was evaluated following 22 weeks of infliximab therapy in 258 patients using the European League Against Rheumatism (EULAR) response criteria. DAS28-CRP (Disease Activity Score including a 28-joint count/C-reactive protein) with a threshold of 4.1 or 2.7 for the high or low disease activity cut-off was also used. A total of 90.3% of patients exhibited high disease activity before infliximab therapy. After 22 weeks of infliximab therapy, the proportions of patients exhibiting high activity, moderate activity, low activity, or in clinical remission were 27.9%, 33.3%, 10.9%, or 27.9%, respectively, thereby indicating good overall efficacy of infliximab therapy. A good or moderate overall response to therapy was achieved in 84.5% of patients. Male sex, rheumatoid factor (RF) negativity, low CRP, lower swollen joint count and a low prednisolone dose were significantly related to the clinical response. Furthermore, male sex, older age, and a high tender joint count had a significant correlation with treatment discontinuation as a result of adverse reactions. In conclusion, we have reconfirmed the effectiveness of infliximab in Japanese patients with RA by using DAS28-CRP and EULAR response criteria. These data will facilitate more efficacious use of this expensive biological agent in the daily practice of rheumatology in Japan. © Japan College of Rheumatology 2007.

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Development and validation of handy rheumatoid activity score with 38 joints (HRAS38) in rheumatoid arthritis patients receiving infliximab

Kameda Hideto, Sekiguchi Naoya, Nagasawa Hayato, Amano Koichi, Takei Hirofumi, Suzuki Katsuya, Nishi Eiko, Ogawa Hiroe, Takeuchi Tsutomu

Modern Rheumatology 16 （ 6 ） 381 - 388 2006年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

The parameters involved in the Disease Activity Score of 28 joints (DAS28) are not mutually independent, and the evaluation excludes ankle and foot joints. We developed a new quantitative and comprehensive assessment of the activity of rheumatoid arthritis (RA), called the handy rheumatoid activity score, with 38 joints (HRAS38), to overcome these disadvantages of DAS28. Forty-six RA patients who recently completed a 1-year infliximab therapy were evaluated for DAS28 (C-reactive protein; CRP) and HRAS38 at 0, 2, 6, 14, 22, 30, 38, 46, and 54 weeks. The 38-joint evaluation in HRAS38 includes 28 joints of DAS28 except for the shoulder joints, with the addition of ankle and metatarsophalangeal joints. The extent of joint swelling was rated on a scale of 0-3. The HRAS38 score is the cumulative sum of three parameters including: (1) a global assessment of disease activity [visual analog scale (VAS) 0-100-mm] by the patient, (2) swollen joint score based on a 38-joint assessment by a physician (0-114), and (3) serum concentration of CRP (mg/l). Scatter plots of HRAS38 and DAS28(CRP), and subsequent linear regression analysis demonstrated a statistically significant correlation between methodologies (r = 0.846, P < 0.0001). Infliximab treatment resulted in a statistically significant (P < 0.001) decrease in the mean HRAS38 score from 130.5 to 56.5 within 2 weeks of treatment and at 52 weeks of therapy scores were still reduced at 52.5. The mean DAS28(CRP) was also significantly (P < 0.001) reduced from a baseline value of 5.8 to 3.7 after 2 weeks treatment with a final value of 3.2 after 52 weeks of therapy. Infliximab reduced the progression of joint destruction by 85%, for terms before infliximab as determined by radiographic analyses. The degree of progression appeared to be associated with the mean HRAS38, although this observation was not shown to be statistically significant by regression analysis (r = 0.307). The HRAS38 score comprises minimal and independently acquired parameters and is an effective and comprehensive measure of disease activity in RA patients. © Japan College of Rheumatology 2006.

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Molecular abnormalities of T-cells in systemic lupus erythematosus

Takeuchi Tsutomu, Tsuzaka Kensei, Kameda Hideto, Amano Kouichi

APLAR Journal of Rheumatology 9 （ 4 ） 365 - 371 2006年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0219-0494

Abstract: Substantial evidence supports that T-cells play a central role in the pathogenesis of systemic lupus erythematosus (SLE). To explore the molecular basis of the defective function of SLE T-cells, we focused on the signal transduction system via T-cell antigen receptor (TCR) in peripheral blood T-cells from SLE patients. Comprehensive analysis to identify the molecules responsible for the defects showed the expression of the TCR ζ chain was attenuated, or absent in more than half of SLE patients. Moreover, the aberrant transcripts of the TCR ζ chain, including spliced variants lacking exon 7 and with a short 3′-UTR, were detected in SLE T-cells. Although attenuated expression of the TCR ζ chain is also observed in patients with cancers, infections, and other autoimmune diseases, sustained attenuation of TCR ζ expression and aberrant transcripts are only observed in SLE. In this review we discuss the unique features of the TCR ζ defects in SLE. © 2006 Asia Pacific League of Associations for Rheumatology.

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TCR zeta mRNA splice variant forms observed in the peripheral blood T cells from systemic lupus erythematosus patients

竹内勤

Springer Seminars In Immunopathology 28 （ 2 ） 185 - 193 2006年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0344-4325

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The efficacy and safety of infliximab in patients equal and over 65 years in the treatment of Japanese 5,000 patients with rheumatoid arthritis.

竹内勤

Arthritis and Rheumatism 54 （ 9 ） S426 - S426 2006年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0004-3591

Aberrant expression of BAFF in T cells of systemic lupus erythematosus, which is recapitulated by a human T cell line, Loucy

Yoshimoto Keiko, Takahashi Yasue, Ogasawara Mie, Setoyama Yumiko, Suzuki Katsuya, Tsuzaka Kensei, Abe Tohru, Takeuchi Tsutomu

International Immunology 18 （ 7 ） 1189 - 1196 2006年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0953-8178

B cell-activating factor of the tumor necrosis factor (TNF) family, or BAFF, is mainly produced in monocytes and dendritic cells, and indispensable for proliferation, differentiation and survival of B cells. BAFF is a type II membrane-bound protein and the extracellular C-terminal fragment is released from the cells as soluble BAFF (sBAFF), which binds to specific receptors on B cells. Accumulating evidence suggests that BAFF plays an important role in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE). In this study, we developed a sensitive sandwich ELISA system to quantify the amount of sBAFF using our own mAb. Treatment of peripheral T cells of SLE patients with an anti-CD3 antibody triggered robust expression of BAFF and subsequent release of sBAFF from the cells. On the other hand, the stimulus induced only marginal elevation of sBAFF from normal T cells. These data indicate that BAFF is expressed in T cells upon stimulation at least under pathological conditions. Expression of BAFF was also largely induced in a human T cell line, Loucy (American Type Tissue Collection CRL-2629), in response to several stimuli, while other T cell lines so far examined produced the cytokine almost constitutively. These data suggest that Loucy recapitulates some of the characteristics of SLE T cells. Investigation of molecular and cellular mechanisms of production of BAFF in Loucy demonstrated that expression of BAFF was regulated through a signal transduction pathway which involves c-jun NH₂-terminal kinase and p38, and that shedding of BAFF was catalyzed by a membrane-bound protease, furin. © 2006 Oxford University Press.

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Elucidation of apoptosis induced by serum deprivation in cultured conjunctival epithelial cells

竹内勤

British Journal OF Opthalmology 90 （ 6 ） 760 - 764 2006年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0007-1161

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Imatinib mesylate inhibits proliferation of rheumatoid synovial fibroblast-like cells and phosphorylation of Gab adapter proteins activated by platelet-derived growth factor

Kameda H., Ishigami H., Suzuki M., Abe T., Takeuchi T.

Clinical and Experimental Immunology 144 （ 2 ） 335 - 341 2006年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0009-9104

Receptors for platelet-derived growth factor (PDGF) are abundantly expressed on synovial fibroblast-like (SFL) cells from patients with rheumatoid arthritis (RA), and stimulation with PDGF enhances both the anchorage-dependent and -independent growth of RA-SFL cells. To elucidate the molecular mechanisms responsible for the excessive growth of RA-SFL cells and to seek a novel molecular-targeting therapy for RA, we examined the expression of adapter proteins and the effect of the specific inhibition of PDGF receptor activation by imatinib mesylate. Cultured SFL cells were used in the present study after 2-5 passages. The anchorage-dependent and -independent growth patterns of the SFL cells were evaluated using a tetrazolium-based assay and colony formation in 0.3% agar, respectively. Adapter proteins Gab1 and Gab2 were expressed in RA-SFL cells, and both proteins were rapidly (< 1 min) tyrosine-phosphorylated after the stimulation of RA-SFL cells with 10 ng/ml of PDGF and, to a lesser extent, after stimulation with 100 ng/ml of epidermal growth factor (EGF). The inhibition of PDGF receptor tyrosine kinase activation by 1 μM or less of imatinib mesylate specifically suppressed the PDGF-dependent, but not EGF-dependent, tyrosine phosphorylation of various proteins. Moreover, imatinib mesylate abolished both the anchorage-dependent and -independent proliferation of RA-SFL cells induced by PDGF stimulation. These results suggest that Gab adapter proteins are expressed and likely to be involved in the growth signalling of rheumatoid synovial cells and that imatinib mesylate, a key drug in the treatment of chronic myeloid leukaemia, may also be effective for the treatment of RA. © 2006 British Society for Immunology.

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Efficacy and safety of bucillamine, a D-penicillamine analogue, in patients with active rheumatoid arthritis

Sekiguchi Naoya, Kameda Hideto, Amano Koichi, Takeuchi Tsutomu

Modern Rheumatology 16 （ 2 ） 85 - 91 2006年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Japanese rheumatologists consider bucillamine (Buc) to be a useful disease-modifying antirheumatic drug (DMARD) and often give Buc to patients with rheumatoid arthritis (RA) prior to administering methotrexate (MTX). However, no large studies on the efficacy and safety of Buc in RA patients have been published in English to date. We therefore investigated the clinical course of RA patients treated with Buc and compared the results with those for patients treated with MTX to evaluate and confirm the place of Buc in therapeutic strategies for RA in Japan. Our results suggested that Buc should be given to patients with moderately active RA either before or after the administration of MTX because its efficacy can be judged within 3 months and because serious adverse events are rare. Issues like the ability of Buc to prevent joint destruction and its efficacy and safety when combined with agents like etanercept require future study. © Japan College of Rheumatology 2006.

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DNA microarray gene expression profile of T cells with the splice variants of TCRζ mRNA observed in systemic lupus erythematosus

Tsuzaka Kensei, Nozaki Kyoko, Kumazawa Chika, Shiraishi Kiyono, Setoyama Yumiko, Yoshimoto Keiko, Suzuki Katsuya, Abe Tohru, Takeuchi Tsutomu

Journal of Immunology 176 （ 2 ） 949 - 956 2006年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0022-1767

We have reported that the TCRζ mRNA with alternatively spliced 3′ UTR (ζ mRNA/as-3′-untranslated region (UTR)) and ζ mRNA lacking exon 7 (ζ mRNA/exon 7-) observed in systemic lupus erythematosus patient T cells can lead to down-regulation of both ζ and TCR/CD3 complexes. To determine whether these T cells expressing decreased ζ exhibit differential transcription patterns, we transfected retrovirus vectors containing wild-type ζ cDNA, ζ cDNA/as-3′ UTR, and ζ cDNA/exon 7- into murine T cell hybridoma MA5.8 cells which lack ζ expression to construct the MA5.8 mutants WT, AS3′ UTR, and EX7-, respectively. FACS analyses demonstrated reduced cell surface expression of ζ and TCR/CD3 complexes on the AS3′ UTR mutant and the EX7- mutant in comparison to that on the WT mutant. Total RNA was collected after stimulating the MA5.8 mutants with anti-CD3 Ab. Reverse-transcribed cDNA was applied to the mouse cDNA microarray containing 8691 genes, and the results were confirmed by real-time PCR. The results showed that 36 genes encoding cytokines and chemokines, including IL-2, IL-15, IL-18, and TGF-β2, were down-regulated in both the AS3′ UTR mutant and the EX7- mutant. Another 16 genes were up-regulated in both, and included genes associated with membranous proteins and cell damage granules, including the genes encoding poliovirus receptor-related 2, syndecan-1, and granzyme A. Increased protein expression of these genes was confirmed by Western blot and FACS analyses. Identification of these responsive genes in T cells in which the ζ and TCR/CD3 complexes were down-regulated may help to better understand the pathogenesis of systemic lupus erythematosus. Copyright © 2006 by The American Association of Immunologists, Inc.

A multicenter, double-blind, randomized, placebo controlled trial of infliximab combined with low dose methotrexate in Japanese patients with rheumatoid arthritis

竹内勤

Journal of Rheumatology 33 （ 1 ） 37 - 44 2006年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

Combination therapy with corticosteroids, cyclosporin A, and intravenous pulse cyclophosphamide for acute/subacute interstitial pneumonia in patients with dermatomyositis

Kameda Hideto, Nagasawa Hayato, Ogawa Hiroe, Sekiguchi Naoya, Takei Hirofumi, Tokuhira Michihide, Amano Koichi, Takeuchi Tsutomu

Journal of Rheumatology 32 （ 9 ） 1719 - 1726 2005年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

Objective. Acute/subacute interstitial pneumonia (A/SIP) in patients with polymyositis/dermatomyositis (PM/DM) is frequently fatal within months despite high dose prednisolone (PSL) therapy. Our objective was to improve the survival rate of patients with A/SIP associated with PM/DM; and to characterize patients with PM/DM who are at high risk of developing A/SIP. Methods. We conducted a pilot trial of combined immunosuppressive therapy with high dose PSL, 10-30 mg/kg of intravenous pulse cyclophosphamide (IVCYC) every 3-4 weeks, and 2-4 mg/kg/day of cyclosporin A (CSA) for patients with A/SIP. A/SIP was diagnosed based on a history of rapidly worsening respiratory symptoms, progressive radiological findings or hypoxemia, and compatible findings in high resolution computed tomography images. Results. Before December 2000, 12 patients with DM among 83 PM/DM patients developed A/SIP, and 9 patients died despite treatment using high dose PSL with or without a choice of CSA, cyclophosphamide, or azathioprine. Thereafter, 10 patients with DM among 27 PM/DM patients developed A/SIP, and they were given combination therapy with PSL, CSA, and IVCYC. Five patients survived and are doing well for more than 2 years, although the remaining 5 patients died of respiratory failure within 3 months. DM patients with A/SIP showed the following characteristic features: mild myositis, palmar papule, fever, and negative or low titer of antinuclear antibody. Conclusion. Immediate institution of intensified immunosuppressive therapy should be considered for patients with A/SIP complicating DM. However, even early recognition of A/SIP and immediate commencement of a regimen including CSA and IVCYC in addition to high dose PSL may not be sufficient for some of those patients.

Critical role of the fifth domain of E-cadherin for heterophilic adhesion with α_Eβ₇, but not for homophilic adhesion

Shiraishi Kiyono, Tsuzaka Kensei, Yoshimoto Keiko, Kumazawa Chika, Nozaki Kyoko, Abe Tohru, Tsubota Kazuo, Takeuchi Tsutomu

Journal of Immunology 175 （ 2 ） 1014 - 1021 2005年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0022-1767

The integrin α_Eβ₇ is expressed on intestinal intraepithelial T lymphocytes and CD8⁺ T lymphocytes in inflammatory lesions near epithelial cells. Adhesion between α_Eβ₇
⁺ T and epithelial cells is mediated by the adhesive interaction of α_Eβ₇ and E-cadherin; this interaction plays a key role in the damage of target epithelia. To explore the structure-function relationship of the heterophilic adhesive interaction between E-cadherin and α_Eβ ₇, we performed cell aggregation assays using L cells transfected with an extracellular domain-deletion mutant of E-cadherin. In homophilic adhesion assays, L cells transfected with wild-type or a domain 5-deficient mutant formed aggregates, whereas transfectants with domain 1-, 2-, 3-, or 4-deficient mutants did not. These results indicate that not only domain 1, but domains 2, 3, and 4 are involved in homophilic adhesion. When α_Eβ₇
⁺ K562 cells were incubated with L cells expressing the wild type, 23% of the resulting cell aggregates consisted of α_Eβ₇
⁺ K562 cells. In contrast, the binding of α_Eβ₇
⁺ K562 cells to L cells expressing a domain 5-deficient mutant was significantly decreased, with α_Eβ₇
⁺ K562 cells accounting for only 4% of the cell aggregates, while homophilic adhesion was completely preserved. These results suggest that domain 5 is involved in heterophilic adhesion with α_Eβ₇, but not in homophilic adhesion, leading to the hypothesis that the fifth domain of E-cadherin may play a critical role in the regulation of heterophilic adhesion to α_Eβ₇ and may be a potential target for treatments altering the adhesion of α_Eβ₇ ⁺ T cells to epithelial cells in inflammatory epithelial diseases. Copyright © 2005 by The American Association of Immunologists, Inc.

A splice variant of the TCR ζ mRNA lacking exon 7 leads to the down-regulation of TCR ζ, the TCR/CD3 complex, and IL-2 production in systemic lupus erythematosus T cells

Tsuzaka Kensei, Setoyama Yumiko, Yoshimoto Keiko, Shiraishi Kiyono, Suzuki Katsuya, Abe Tohru, Takeuchi Tsutomu

Journal of Immunology 174 （ 6 ） 3518 - 3525 2005年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0022-1767

The reduction or absence of TCR ζ-chain (ζ) expression in patients with systemic lupus erythematosus (SLE) is thought to be a factor in the pathogenesis of SLE. We previously reported a splice variant of ζ mRNA that lacks the 36-bp exon 7 (ζ mRNA/exon 7(-)) and is accompanied by the down-regulation of ζ protein in T cells from SLE patients. In this study, we show that EX7-mutants (MA5.8 cells deficient in ζ protein that have been transfected with ζ mRNA/exon 7(-)) exhibit a reduction in the expression of TCR/CD3 complex and ζ protein on their cell surface as well as a reduction in the production of IL-2 after stimulation with anti-CD3 Ab, compared with that in wild-type (WT) mutants (MA5.8 cells transfected with the WT ζ mRNA). Furthermore, real-time PCR analyses demonstrated that ζ mRNA/exon 7(-) in EX7- mutants was easily degraded compared with ζ mRNA by the WT mutants. Pulse-chase experiment showed ζ protein produced by this EX7- mutants was more rapidly decreased compared with the WT mutants. Thus, the lower stability of ζ mRNA/exon 7(-) might also be responsible for the reduced expression of the TCR/CD3 complex, including ζ protein, in SLE T cells. Copyright © 2005 by The American Association of Immunologists, Inc.

Official Japanese guidelines for the use of infliximab for rheumatoid arthritis

Miyasaka Nobuyuki, Takeuchi Tsutomu, Eguchi Katsumi

Modern Rheumatology 15 （ 1 ） 4 - 8 2005年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Differences in ethnic backgrounds as well as in medical and socioeconomic status often affect both the efficacy and adverse effects of medications. Recent data suggest an increased risk of opportunistic infections, especially tuberculosis (TB), among rheumatoid arthritis (RA) patients receiving infliximab, a chimeric monoclonal anti-tumor necrosis factor α (TNF-α) antibody. In this regard, the annual incidence of TB is approximately five times higher in Japan than in the United States. Furthermore, since Bacillus Calmette-Guérin vaccination is mandatory in childhood when the skin test for purified protein derivative (PPD) is negative, a high incidence of false-positive PPD skin tests is observed among the Japanese population. In addition, the upper limit of methotrexate dosage to be used for RA is lower in Japan. We have therefore established official guidelines for the proper use of infliximab in Japanese RA patients. In this review, an algorithm for the diagnosis and management of TB in RA is presented in an evidenced-based form. © Japan College of Rheumatology and Springer-Verlag Tokyo 2005.

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Factors predicting the response to low-dose methotrexate therapy in patients with rheumatoid arthritis

Kameda Hideto, Amano Koichi, Sekiguchi Naoya, Takei Hirofumi, Ogawa Hiroe, Nagasawa Hayato, Takeuchi Tsutomu

Modern Rheumatology 14 （ 6 ） 442 - 446 2004年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug (DMARD) throughout the world. In Japan, MTX is recommended by the Japanese Ministry of Health, Labour, and Welfare to be given as the second or third DMARD and at a dosage of no more than 8 mg/week. We analyzed the efficacy of MTX in Japanese patients with RA in order to determine whether it is comparable to that in Western countries, where 15-20 mg/week of MTX is used, as well as to elucidate the factors associated with the favorable response to MTX. Around 8 mg/week of MTX was effective in half of the RA patients in the current study, and male sex was the only factor associated with a good response to MTX from a multivariate regression model analysis. Some of the patients who had a poor response to MTX showed an improvement with the addition of bucillamine or prednisolone. For the remaining patients, an increase in the MTX dosage to more than 8 mg/week or the use of biologics such as the anti-tumor necrosis factor (TNF)-α monoclonal antibody may be required. © Japan College of Rheumatology and Springer-Verlag Tokyo 2004.

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Incidence of cytomegalovirus reactivation in patients with inflammatory connective tissue diseases who are under immunosuppressive therapy

Mori Takehiko, Kameda Hideto, Ogawa Hiroe, Iizuka Atsushi, Sekiguchi Naoya, Takei Hirofumi, Nagasawa Hayato, Tokuhira Michihide, Tanaka Toshio, Saito Yumiko, Amano Koichi, Abe Toru, Takeuchi Tsutomu

Journal of Rheumatology 31 （ 7 ） 1349 - 1351 2004年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

Objective. To evaluate the incidence and effect of cytomegalovirus (CMV) reactivation in patients with inflammatory connective tissue diseases (CTD) undergoing immunosuppressive therapy. Methods. A total of 18 consecutive CMV seropositive patients undergoing immunosuppressive therapy for inflammatory CTD were enrolled. CMV reactivation was determined by detection of CMV-DNA in peripheral blood leukocytes (PBL) or plasma using quantitative real-time polymerase chain reaction. Results. CMV reactivation was detected in PBL in 7 of 17 evaluable patients (41%), and in plasma in 5 of 17 patients (29%). Patients with detectable CMV-DNA in plasma were exclusively positive for CMV-DNA in PBL. Conclusion. Patients with inflammatory CTD under immunosuppressive therapy are at high risk for CMV reactivation. The clinical significance of such an event and indications for antiviral therapy should be examined further.

Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody

Nishimoto Norihiro, Yoshizaki Kazuyuki, Miyasaka Nobuyuki, Yamamoto Kazuhiko, Kawai Shinichi, Takeuchi Tsutomu, Hashimoto Jun, Azuma Junichi, Kishimoto Tadamitsu

Arthritis and Rheumatism 50 （ 6 ） 1761 - 1769 2004年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0004-3591

Objective. Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates the immune response, inflammation, and hematopoiesis. Overproduction of IL-6 plays pathologic roles in rheumatoid arthritis (RA), and the blockade of IL-6 may be therapeutically effective for the disease. This study was undertaken to evaluate the safety and efficacy of a humanized anti-IL-6 receptor antibody, MRA, in patients with RA. Methods. In a multicenter, double-blind, placebo-controlled trial, 164 patients with refractory RA were randomized to receive either MRA (4 mg/kg body weight or 8 mg/kg body weight) or placebo. MRA was administered intravenously every 4 weeks for a total of 3 months. The clinical responses were measured using the American College of Rheumatology (ACR) criteria. Results. Treatment with MRA reduced disease activity in a dose-dependent manner. At 3 months, 78% of patients in the 8-mg group, 57% in the 4-mg group, and 11% in the placebo group achieved at least a 20% improvement in disease activity according to the ACR criteria (an ACR20 response) (P < 0.001 for 8-mg group versus placebo). Forty percent of patients in the 8-mg group and 1.9% in the placebo group achieved an ACR50 response (P < 0.001). The overall incidences of adverse events were 56%, 59%, and 51% in the placebo, 4-mg, and 8-mg groups, respectively, and the adverse events were not dose dependent. A blood cholesterol increase was observed in 44.0% of the patients. Liver function disorders and decreases in white blood cell counts were also observed, but these were mild and transient. There was no increase in antinuclear antibodies or anti-DNA antibodies. Anti-MRA antibodies were detected in 2 patients. Conclusion. Treatment with MRA was generally well tolerated and significantly reduced the disease activity of RA.

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TCRζ mRNA with an alternatively spliced 3′-untranslated region detected in systemic lupus erythematosus patients leads to the down-regulation of TCRζ and TCR/CD3 complex

Tsuzaka Kensei, Fukuhara Izumi, Setoyama Yumiko, Yoshimoto Keiko, Suzuki Katsuya, Abe Tohru, Takeuchi Tsutomu

Journal of Immunology 171 （ 5 ） 2496 - 2503 2003年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0022-1767

The reduction or absence of TCR ζ-chain (ζ) expression in systemic lupus erythematosus (SLE) patients is thought to be related to the pathogenesis of SLE. Recently, we reported the predominant expression of ζ mRNA containing an alternatively spliced 3′-untranslated region (3′UTR; ζmRNA/as-3′UTR) and a reduction in the expression of ζ mRNA containing the wild-type 3′UTR (ζmRNA/w-3′UTR) in T cells from SLE patients. Here we show that AS3′UTR mutants (MA5.8 cells deficient in ζ protein that have been transfected with ζmRNA/as-3′UTR) exhibit a reduction in the expression of TCR/CD3 complex and ζ protein on their cell surface as well as a reduction in the production of IL-2 after stimulation with anti-CD3 Ab compared with that in wild-type 3′UTR mutants (MA5.8 cells transfected with ζmRNA/w-3′UTR). Furthermore, the real-time PCR analyses demonstrated that the half-life of ζmRNA/as-3′UTR in AS3′UTR mutants (3 h) was much shorter than that of ζmRNA/w-3′UTR in wild-type 3′UTR mutants (15 h). Thus, the lower stability of ζmRNA/as-3′UTR, which is predominant in SLE T cells, may be responsible for the reduced expression of the TCR/CD3 complex, including ζ protein, in SLE T cells.

Abnormal protein profiles in tears with dry eye syndrome

Ohashi Yoshiki, Ishida Reiko, Kojima Takashi, Goto Eiki, Matsumoto Yukihiro, Watanabe Katsuhiko, Ishida Naruhiro, Nakata Katsuhiko, Takeuchi Tsutomu, Tsubota Kazuo

American Journal of Ophthalmology 136 （ 2 ） 291 - 299 2003年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0002-9394

PURPOSE: To verify the hypothesis that protein concentrations, such as lactoferrin, epidermal growth factor (EGF), and aquaporin 5 (AQP5), in tears are abnormal in patients with dry eye. DESIGN: Prospective case-control study. METHODS: One hundred three dry eye patients were divided into three groups: dry eye not associated with the Sjögren syndrome (non-SS; n = 71), Sjögren syndrome (SS; n = 23), and Stevens-Johnson syndrome (SJS; n = 9). Sixteen normal control subjects were also checked. The concentrations of lactoerrin, EGF, and AQP5 were measured by enzyme-linked immunosorbent assay. RESULTS: The concentration of lactoferrin was significantly decreased in tears of non-SS (P = .0001), SS (P = .00005), and SJS (P = .0006) patients compared with control subjects. The concentration of EGF was significantly decreased in non-SS (P = .0005), SS (P = .00002), and SJS (P = .0001) patients compared with control subjects. The concentration of AQP5 was significantly increased in tears of only SS patients (P = .01) compared with control subjects and increased in tears of only SS patients compared with non-SS patients (P = .007). CONCLUSIONS: The decrease in both lactoferrin and EGF was found not only in SS patients but also in non-SS patients, indicating that tear components in dry eyes differ in their quantity and quality. Quantification of AQP5 increased only in SS patients, suggesting that AQP5 protein leaks into the tears when acinar cells of the lacrimal gland are damaged by lymphocytic infiltration. © 2003 by Elsevier Inc. All rights reserved.

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Quantitative analysis of lacrimal gland function, apoptotic figures, Fas and Fas ligand expression of lacrimal glands in dry eye patients

竹内勤

Experimental Eye Research 76 （ 2 ） 233 - 240 2003年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0014-4835

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Pathogenic roles of IL-6 and IL-6 blocking therapy on rheumatoid arthritis

竹内勤

Arthritis Research and Therapy 5 S42 2003年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1478-6354

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Rapid proliferation of a different clone early after autologous peripheral blood stem cell transplantation for non-hodgkin's lymphoma

Mori Takehiko, Tamaru Junichi, Tokuhira Michihide, Mori Shigehisa, Suzuki Hiroshi, Abe Toru, Takeuchi Tsutomu

International Journal of Hematology 76 （ 3 ） 287 - 289 2002年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0925-5710

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Rapid proliferation of a different clone early after autologous peripheral blood stem cell transplantation for non-Hodgkin's lymphoma

竹内勤

International Journal of Hematology 76 （ 3 ） 287 - 289 2002年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0925-5710

Successful non-surgical treatment of brain abscess and necrotizing fasciitis caused by Bacillus cereus

Mori Takehiko, Tokuhira Michihide, Takae Yujiro, Mori Shigehisa, Suzuki Hirosi, Abe Toru, Takeuchi Tsutomu

Internal Medicine 41 （ 8 ） 671 - 673 2002年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0918-2918

Musculoskeletal and central nervous system infections caused by Bacillus cereus are very rare. Only a few cases have been reported, whose clinical courses strongly suggested that surgical procedures combined with appropriate antimicrobial therapy are necessary to cure these infections. A 60-year-old man with severe neutropenia due to myelodysplastic syndrome, developing necrotizing fasciitis and brain abscess caused by Bacillus cereus is reported. Without performing any surgical procedures, the patient was successfully treated with systemic antimicrobial therapy combined with granulocyte colony stimulating factor, which contributed to the increase in the neutrophil count.

CD30 and the NPM-ALK fusion protein (p80) are differentially expressed between peripheral blood and bone marrow in primary small cell variant of anaplastic large cell lymphoma

竹内勤

American Journal of Hematology 69 （ 3 ） 200 - 204 2002年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0361-8609

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T-cell receptor ζ mRNA with an alternatively spliced 3′ untranslated region is generated predominantly in the peripheral blood T cells of systemic lupus erythematosus patients

Tsuzaka Kensei, Onoda Natsuko, Yoshimoto Keiko, Setoyama Yumiko, Suzuki Katsuya, Pang Ming, Abe Tohru, Takeuchi Tsutomu

Modern Rheumatology 12 （ 2 ） 167 - 173 2002年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

To investigate the mechanism of the downregulation of T-cell receptor ζ chain (TCRζ) expression in the peripheral blood T cells (PBTs) of systemic lupus erythematosus (SLE) patients, we analyzed the 3′ untranslated region (3′UTR) of TCRζ mRNA, because the 3′UTR in mRNA is responsible for posttranscriptional regulation. Use of the reverse transcriptase polymerase chain reaction (RT-PCR) to amplify the 917bp TCRζ 3′UTR cDNA demonstrated that the short variant cDNA (355bp), expressed as an alternatively spliced 3′UTR with 562-bp deletion, was predominated in the PBTs of 11 of 14 SLE patients, whereas mainly the wild-form cDNA (917bp) was detected in the PBTs of seven negative controls (two systemic sclerosis patients, five normal controls) and in two T-cell line hybridomas. Semiquantitative PCR also revealed the predominant expression of the TCRζ mRNA with alternatively spliced 3′UTR (TCRζ mRNA/as-3′UTR), and a decreased expression of TCRζ mRNA with the wild form 3′UTR (TCRζ mRNA/w-3′UTR) in SLE T cells. However, there was no difference in the expression of the open reading frame (ORF) TCRζ mRNA between the negative controls and SLE patients. The TCRζ protein expression level according to Western blot analysis correlated well with that of TCRζ mRNA/w-3′UTR (r = 0.931) and reversibly with TCRζ mRNA/as-3′UTR (r = -0.614), but not with ORF TCRζ mRNA (r = -0.296). It can be concluded that the reduced expression of TCRζ mRNA/w-3′UTR and the pre-dominant expression of TCRζ mRNA/as-3′UTR lead to downregulation of the TCRζ protein in SLE T cells.

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Abnormal expression and function of Fas ligand of lachrymal glands and peripheral blood in Sjögren's syndrome patients with enlarged exocrine glands

Tsubota K., Fujita H., Tadano K., Onoda N., Tsuzaka K., Takeuchi T.

Clinical and Experimental Immunology 129 （ 1 ） 177 - 182 2002年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0009-9104

The objective of our study was to investigate the possibility of Fas ligand protein abnormalities in certain types of Sjögren's syndrome patients with enlarged exocrine glands. Fas ligand expression by lymphocytes infiltrating the lachrymal glands and by peripheral blood monocytes in Sjögren's syndrome patients with enlarged exocrine glands was assessed immunohistologically and by immunoblotting. Cytotoxicity of peripheral blood monocytes and sensitivity to steroids in Sjögren's syndrome patients with enlarged exocrine glands were studied by functional assay. Minimal Fas ligand expression was detected in the lymphocytes of the lachrymal glands and a decreased level of Fas ligand was found in peripheral blood monocytes as assessed by immunoblotting. Functional assay confirmed the decreased cytotoxicity of lymphocytes in Sjögren's syndrome patients with enlarged exocrine glands, and that it is not affected by anti-Fas ligand antibody. By contrast, the sensitivity of lymphocytes in Sjögren's syndrome patients with enlarged exocrine glands to steroids was increased. These observations suggest that abnormal expression and function of Fas ligand occurs in Sjögren's syndrome patients with enlarged exocrine glands.

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Defective expression and tyrosine phosphorylation of the T cell receptor zeta chain in peripheral blood T cells from systemic lupus erythematosus patients

Pang M., Setoyama Y., Tsuzaka K., Yoshimoto K., Amano K., Abe T., Takeuchi T.

Clinical and Experimental Immunology 129 （ 1 ） 160 - 168 2002年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0009-9104

We have reported that tyrosine phosphorylation and expression of the T cell receptor zeta chain (TCR ζ) was decreased in two systemic lupus erythematosus (SLE) patients with an abnormal TCR ζ lacking exon-7. To examine further the TCR ζ defect and any possible relationship with specific clinical features, we studied the expression of TCR ζ in peripheral blood T cells from 44 patients with SLE, 53 with other rheumatic diseases (30 rheumatoid arthritis (RA), 11 systemic sclerosis (SSc) and 12 primary Sjögren's syndrome(SjS)) and 39 healthy individuals. Flow cytometric analysis demonstrated a significant decrease in the expression of TCR ζ in SLE (P < 0.001), but not in the other rheumatic diseases. Immunoprecipitation experiments confirmed that the expression of TCR ζ in SLE T cells was decreased dramatically (normal: 111.4 ± 22.6%, SLE: 51.6 ± 37.4%,P < 0.0001). The decrease in TCR ζ did not correlate with disease activity, or with the dose of prednisolone (PSL). There were, however, three SLE patients in whom the level of TCR ζ expression normalized after treatment, suggesting that mechanisms responsible for the TCR ζ defect appear to be heterogeneous. These results confirm the defective expression and altered tyrosine phosphorylation of TCR ζ in a large proportion of SLE patients, suggesting that it may play an important role in T cell dysfunction in SLE.

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A functional polymorphism in Fas (CD95/APO-1) gene promoter associated with systemic lupus erythematosus

Kanemitsu Satomi, Ihara Kenji, Saifddin Ahmed, Otsuka Takeshi, Takeuchi Tsutomu, Nagayama Jun, Kuwano Michihiko, Hara Toshiro

Journal of Rheumatology 29 （ 6 ） 1183 - 1188 2002年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

Objective. To investigate whether Fas promoter polymorphisms show a genetic contribution to the development of systemic lupus erythematosus (SLE) in a Japanese population, and to study the functional difference in promoter activity of the polymorphisms. Methods. In 109 SLE patients and 140 controls, the frequencies of A/G polymorphisms at -670 nucleotide position and G/A at -1377 nucleotide position were determined by allele-specific polymerase chain reaction (PCR) or PCR-single strand conformation polymorphism analysis. The functional significance of the -670A/G polymorphism in the Fas gene was evaluated by a combination of Fas transcriptional activity in the reporter gene assay and binding activity of signal transducer and activator of transcription (STAT)1 protein in the electrophoretic mobility shift assay. Results. SLE patients exhibited significantly higher frequency of A allele at nucleotide position -670 (p = 0.004). There was no significant difference in the nucleotide position -1377 in Fas promoter gene between SLE patients and controls. The electrophoretic mobility shift assay demonstrated that the oligonucleotide with -670A in the Fas promoter had a higher binding ability to a GAS binding protein, STAT1, than that with -670G, although there was no statistically significant difference in the reporter gene assay. Conclusion. Fas promoter -670A/G polymorphism was significantly associated with SLE, suggesting a possibility that Fas promoter contributes, at least in part, to the pathogenesis of SLE.

Diagnostic significance of serum soluble transferrin receptors in various anemic diseases

Matsuda Akira, Besso Masami, Mori Shigehisa, Takeuchi Tsutomu, Abe Tohru, Yawata Yoshihito, Mori Hiraku, Omine Mitsuhiro, Nakamura Yuichi, Furusawa Shinpei, Maeda Teiryo, Haginosita Susumu, Hirasawa Yoshihei, Kinugasa Eriko, Akizawa Tadao, Kawakami Naohito, Nagata Atsuo, Hirashima Kunitake

Haematologia 32 （ 3 ） 225 - 238 2002年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0017-6559

Serum soluble transferrin receptor (sTfR) has been reported to be higher in patients with iron deficiency or with elevated erythropoiesis. In the present study, serum sTfR was measured in various anemic diseases and their clinical significance was examined in a multi-institutional joint study. Serum sTfRs in patients with the following anemic diseases were markedly higher than those in normal healthy adults: non-treated iron deficiency anemia (IDA) (9.13 ± 7.04 mg/l, n = 52, p <0.0001), anemia of chronic disorders (ACD) (3.45 ± 1.38 mg/l, n = 20, p <0.0001), hemolytic anemia (HA) (5.57 ± 3.26 mg/l, n = 17, p <0.0001), and myelodysplastic syndrome (MDS) (4.03 ± 2.83 mg/l, n = 20, p <0.0001). There were significant differences between IDA and ACD (p <0.0001), between aplastic anemia (AA) (1.58 ± 1.26 mg/l, n = 16) and MDS (p <0.001), and between AA and MDS with refractory anemia (MDS-RA) (4.16 ± 3.40 mg/l, n = 9) (p <0.02). In patients with chronic renal failure (CRF), serum sTfR levels and serum sTfR/log serum ferritin ratios (sTfR/F index) were compared in the two classified groups according to Muirhead's criteria, as IDA and non-IDA groups with or without recombinant human erythropoietin (rHuEPO) treatment. Significantly high levels of both serum sTfR (p <0.0001) and the sTfR/F index (p <0.0001) were observed in IDA without rHuEPO treatment. Especially in CRF with rHuEPO treatment, the sTfR/F index showed marked elevation in the IDA group (p <0.0001) compared with serum sTfR (p <0.001), indicating more diagnostic efficacy of the sTfR/F index for CRF with IDA. In conclusion, the serum sTfR concentration is a useful diagnostic tool for discrimination between IDA and ACD, and between AA and MDS-RA, and for the detection of iron deficiency in CRF patients in the Japanese population.

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Primary natural killer cell lymphoma of the lacrimal sac

竹内勤

Annals of Hematology 80 （ 10 ） 607 - 610 2001年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0939-5555

Expression of Gab1 lacking the pleckstrin homology domain is associated with neoplastic progression

竹内勤

Molecular and Cellular Biology 21 （ 20 ） 6895 - 6905 2001年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0270-7306

Successful treatment of embryo implantation failure in patients with the Sjogren syndrome with low-dose prednisolone

竹内勤

Fertility and Sterility 75 （ 3 ） 640 - 641 2001年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0015-0282

Improvement of lacrimal function by topical application of CyA in murine models of Sjögren's syndrome

Tsubota K., Fujita H., Tadano K., Takeuchi T., Murakami T., Saito I., Hayashi Y.

Investigative Ophthalmology and Visual Science 42 （ 1 ） 101 - 110 2001年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0146-0404

PURPOSE. The object of this study was to evaluate improvement of lacrimal gland (LG) function after topical cyclosporin A (CyA). METHODS. Topical CyA (0.01% and 0.1%) was applied to two mouse models of Sjögren's syndrome, the NFS/sld after thymectomy and the nonobese diabetic (NOD) mouse, and the functional integrity of the lacrimal gland was evaluated by measuring basal and stimulated tear secretion and its histologic integrity by examining it for apoptosis and lymphocyte invasion. RESULTS. After treatment with CyA 0.1% in the NFS/sld mice, tear function increased, and there was a decrease in lymphocyte infiltration of the LG and a decrease in apoptotic figures among the acinar cells. In the NOD mice, tear function also improved, but there was no associated decrease in lymphocyte infiltration. However, the expression of Fas ligand (FasL) in NOD mice by infiltrating lymphocytes was suppressed with 0.1% CyA eye drops. CONCLUSIONS. CyA appears to improve tear secretion in mouse models of Sjögren's syndrome by preventing lymphocyte-induced apoptosis of acinar cells in one model this was achieved by preventing lymphocyte infiltration and in the other by reducing expression of FasL expression on infiltrating lymphocytes.

Levels of interleukin-18 and its binding inhibitors in the blood circulation of patients with adult-onset Still's disease

Kawashima Masanori, Yamamura Masahiro, Taniai Madoka, Yamauchi Hiroshi, Tanimoto Tadao, Kurimoto Masashi, Miyawaki Shoji, Amano Tetsuki, Takeuchi Tsutomu, Makino Hirofumi

Arthritis and Rheumatism 44 （ 3 ） 550 - 560 2001年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0004-3591

Objective. Interleukin-18 (IL-18) is a proinflammatory cytokine that is involved in immunologically mediated tissue damage, but its bioactivity is regulated in vivo by its soluble decoy receptor, IL-18 binding protein (IL-18BP). This study was undertaken to determine levels of IL-18 and IL-18 binding inhibition in the blood of patients with adult-onset Still's disease (ASD). Methods. Serum concentrations of IL-18 in ASD patients were compared by enzyme-linked immunosorbent assay (ELISA) with those in patients with other systemic rheumatic diseases and healthy controls. The biologically active mature protein of IL-18 was detected by Western blot analysis with anti-IL-18 antibody and its induction of interferon-γ (IFNγ) secretion from IL-18-responding human myelomonocytic KG-1 cells. The inhibitory activity on IL-18 binding to its receptor was determined by ¹²⁵I-IL-18 binding inhibition assay using the Chinese hamster ovary cell line transfected with a murine IL-18 receptor (CHO-K1/mIL-18R). Results. Concentrations of serum IL-18 were extremely elevated in patients with active ASD compared with those in patients with rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, polymyositis/dermatomyositis, Sjögren's syndrome, or healthy individuals. Levels of IL-18 were found to correlate with serum ferritin values and disease severity in ASD. Western blot analysis revealed that serum samples from patients with active ASD contained an 18-kd polypeptide of IL-18, corresponding in size to the mature form. Accordingly, the samples were able to induce IFNγ secretion from KG-1 cells, which was largely abolished by neutralizing anti-IL-18 antibody. However, the level of IL-18 bioactivity was more than 10-fold weaker than the concentration of IL-18 protein measured by ELISA. Serum samples from patients with active ASD showed an inhibitory effect on the binding of ¹²⁵I-IL-18 to CHO-K1/mIL-18R cells, and this activity was associated with elevation of IL-18. Conclusion. These data indicate that systemic overproduction of IL-18 may be closely related to the pathogenesis of ASD, despite the restriction on its inflammatory activity by IL-18 binding inhibitors such as IL-18BP. The disease activity appears to be determined on the basis of the relative levels of IL-18 and its specific inhibitors.

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Successful treatment of embryo implantation failure in patients with the Sjögren syndrome with low-dose prednisolone

Ishihara Osamu, Saitoh Masahiro, Hayashi Naoki, Kinoshita Katsuyuki, Takeuchi Tsutomu

Fertility and Sterility 75 （ 3 ） 640 - 641 2001年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0015-0282

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Association of CTLA-4 but not CD28 gene polymorphisms with systemic lupus erythematosus in the Japanese population

Ahmed S., Ihara K., Kanemitsu S., Nakashima H., Otsuka T., Tsuzaka K., Takeuchi T., Hara T.

Rheumatology 40 （ 6 ） 662 - 667 2001年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1462-0324

Objective. Systemic lupus erythematosus (SLE) in a multisystem autoimmune disorder characterized by multiorgan pathology and autoantibodies against a variety of autoantigens. The CD28 and CTLA-4 genes might be candidate genes for SLE, because costimulation signals from CD80/CD86 to CD28/CTLA-4 have been suggested to play an important role in the activation or inactivation of T lymphocytes. Methods. We investigated three polymorphic regions within the CTLA-4 gene, a C/T base exchange in the promoter region - 318 (CTLA-4 - 318C/T), an A/G substitution in the exon 1 position 49 (CTLA-4 49A/G), an (AT)_n repeat polymorphism in the 3′ untranslated region of exon 4 [CTLA-4 3′ (AT)_n], and a CD28 gene polymorphism, a T/C substitution in the intron 3 position + 17 (CD28 IVS3 + 17T/C), in SLE patients and controls. Results. SLE patients had significantly higher frequencies of the CTLA-4 49G allele (P = 0.003) and of the CTLA-4 (AT)_n 106 bp allele (P = 0.0008) than controls. We also found a strong linkage disequilibrium between the A allele of CTLA-4 49A/G and the 86 bp allele of CTLA-4 3′ (AT)_n. On the contrary, no association was found between SLE and CTLA-4 -318C/T or CD28 IVS3 + 17T/C. Conclusion. We conclude that the CTLA-4 gene appears to play a significant role in the development of SLE in the Japanese population.

Complement component 9 deficiency is not a susceptibility factor for SLE

竹内勤

LUPUS 9 （ 6 ） 456 - 457 2000年

研究論文（学術雑誌）, ISSN 0961-2033

Mikulicz's disease and Sjogren's syndrome

Tsubota Kazuo, Fujita Hiromi, Tsuzaka Kensei, Takeuchi Tsutomu

Investigative Ophthalmology and Visual Science 41 （ 7 ） 1666 - 1673 2000年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0146-0404

PURPOSE. To characterize lacrimal gland function and lymphocyte infiltration in patients with Mikulicz's disease (MD) and Sjogren's syndrome (SS). METHODS. Four patients with MD and 5 with SS were recruited, on whom were performed Schirmer test I (Schirmer test without anesthesia), Schirmer test with nasal stimulation, and vital staining of the ocular surface. The lacrimal gland was then biopsied and the tissues stained with CD3, CD4, CD8, B220, APO2.7, Fas, and Fas ligand (Fas-L) antibodies. RESULTS. Although regular Schirmer test results in the MD group were less than 10 mm, those with nasal stimulation, 38.1 ± 3.4 mm, were significantly greater than the SS group. There were minimal ocular surface changes in MD. Morphologic staining with hematoxylin and eosin was identical in both groups, but the acinar cells were stained with APO2.7 only in the SS group. There was strong Fas and Fas-L staining in SS patients but not in those with MD. CONCLUSIONS. Lacrimal gland acinar cells in those with MD maintained their function and were not programmed for cell death. The sicca syndrome was not observed in MD patients. Although the pathology is similar for MD and SS, the difference in acinar cell apoptosis and function can explain clinical differences.

Serum levels of IFN-inducible protein-10 relating to the activity of systemic lupus erythematosus

Narumi Shosaku, Takeuchi Tsutomu, Kobayashi Yuko, Konishi Konosuke

Cytokine 12 （ 10 ） 1561 - 1565 2000年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1043-4666

IFN-inducible protein-10 (IP-10) is supposed to act as a specific chemoattractant for Th₁ cells. Since Th₁ cells and IFN-γ are shown to be important for developing systemic lupus erythematosus (SLE), we examined the relationship between serum IP-10 levels and the disease activity. Serum IP-10 levels were markedly increased in the SLE patients depending on the level of disease activity, whereas not in the patients with rheumatoid arthritis (RA). On the other hand, serum MCP-1 levels were increased to a similar extent both in RA and inactive SLE patients, and a little more elevated in active SLE patients. Serum IP-10 levels in SLE patients correlated positively and negatively with levels of anti-DNA antibody and complements, respectively, whereas MCP-1 levels correlated less or not at all. These results suggest that serum IP-10 levels could be a good indicator for the activity of SLE and that IP-10 could play an important immunological role in SLE. (C) 2000 Academic Press.

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Nosocomial pneumonia likely caused by Stenotrophomonas maltophilia in two patients with polymyositis

Amano Koichi, Maruyama Hiroshi, Takeuchi Tsutomu

Internal Medicine 38 （ 11 ） 910 - 916 1999年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0918-2918

We report two cases of polymyositis (PM) complicated with nosocomial pneumonia probably caused by Stenotrophomonas maltophilia, which was resistant to multiple antimicrobials. In the first case, the chest CT findings and high serum endotoxin level as well as sputum culture results were helpful for the proper diagnosis and the therapy was successful. However the second patient died of a lung abscess in spite of the intensive antibiotic therapy. When PM patients develop pneumonia unresponsive to various antibiotics, a multi-drug-resistant bacteria such as Stenotrophomonas maltophilia should be considered as the pathogen.

Preferential localization of CD8⁺ α(E)β₇⁺ T cells around acinar epithelial cells with apoptosis in patients with Sjogren's syndrome

Fujihara Tsutomu, Fujita Hiromi, Tsubota Kazuo, Saito Keiko, Tsuzaka Kensei, Abe Tohru, Takeuchi Tsutomu

Journal of Immunology 163 （ 4 ） 2226 - 2235 1999年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0022-1767

The T lymphocytes that infiltrate the exocrine glands in Sjogren's syndrome (SS) play a key role in damaging glandular epithelial cells, but the mechanisms of tiffs damage by T lymphocytes are not fully understood. To determine the cellular basis of this phenomenon, we focused our attention on the T lymphocytes around acinar epithelial cells in SS. We showed that CD8⁺ but not CD4⁺ T lymphocytes were located around the acinar epithelial cells and that a majority of these CD8⁺ T lymphocytes possess an unique integrin, α(E)β₇ (CD103). The acinar epithelial cell adherent with α(E)β₇ (CD103)+ CD8⁺ T lymphocytes was apoptotic. Both the perforin/granzyme B and Fas/Fas ligand pathways were implicated in the process of programmed cell death in lacrimal glands. These results suggested that α(E)β₇ integrin, by interacting with E-cadherin, mediates the adhesion between CD8⁺ T lymphocytes and acinar epithelial cells in SS and participates in inducing epithelial cell apoptosis, leading to secretory dysfunction of exocrine glands, a hallmark of SS.

1-2). Defective signal transduction via TCR-CD3 complex in patients with systemic lupus erythematosus

Takeuchi Tsutomu, Tsuzaka Kensei, Pang Ming, Abe Tohru

Internal Medicine 38 （ 2 ） 169 1999年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0918-2918

Candida pneumonia in a case of polymyositis complicated with interstitial pneumonitis

Takano Y., Amano K., Aoki K., Takeuchi T.

Japanese Journal of Rheumatology 9 （ 4 ） 397 - 402 1999年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0169-1163

We report a polymyositis patient who developed Candida pneumonia, whose clinical manifestations such as dry cough, dyspnea, fever and elevated LDH looked like a recurrence of interstitial pneumonitis (IP) which she had had at admission. The distribution of the lesions in high resolution computed tomography scan, the high serum level of β-D-glucan and positive Candida antigen test led to make a diagnosis of Candida pneumonia rather than IP, and fluconazole therapy was successful.

Regulation of human leukocyte antigen expression in human conjunctival epithelium

Tsubota Kazuo, Fukagawa Kazumi, Fujihara Tsutomu, Shimmura Shigeto, Saito Ichiro, Saito Keiko, Takeuchi Tsutomu

Investigative Ophthalmology and Visual Science 40 （ 1 ） 28 - 34 1999年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0146-0404

Purpose. To demonstrate that interferon-γ (IFN-γ) is the key cytokine responsible for the upregulation of HLA-DR antigen in conjunctival epithelial cells of Sjogren syndrome (SS) patients. Methods. Flow cytometry of conjunctival epithelial cells from SS and non-SS dry eye patients was performed for the quantification of HLA-DR surface expression. With a conjunctival epithelial cell line (ChWK), HLA-DR regulation by various cytokines was evaluated, and confocal immunocytochemical and western blot analyses were performed to evaluate the activation of nuclear factor-kappa B (NF-κB) and signal transducers and activators of transcription 1 and 3 (STAT1 and STAT3, respectively). Results. HLA-DR expression was upregulated in conjunctival epithelial cells of SS patients but not in non-SS dry eye patient or healthy control subject. IFN-γ was the only cytokine that effectively upregulated HLA-DR expression in ChWK, which was synergistically enhanced by tumor necrosis factor-α (TNF-α). IFN-γ induced the nuclear translocation of NF-κB, but did not activate STAT1 or STAT3 in ChWk. Conclusions. Upregulation of HLA-DR antigen in the conjunctival epithelium of SS patients may be regulated by IFN-γ through the activation of NF-κB.

Conjunctival epithelium expression of HLA-DR in dry eye patients

Tsubota Kazuo, Fujihara Tsutomu, Saito Keiko, Takeuchi Tsutomu

Ophthalmologica 213 （ 1 ） 16 - 19 1999年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0030-3755

Purpose: To compare conjunctival epithelium expression of HLA-DR and ICAM-1 with tear dynamics and ocular surface parameters. Methods: Brush cytology and flow cytometry were used to quantitatively analyze HLA-DR and ICAM-1 expression in 28 dry eye patients. Results: HLA-DR was expressed in 66% of the conjunctival cells of dry eye patients. This expression correlates with that of ICAM-1, as well as with the Schirmer test results (p<0.05). Conclusion: This study confirmed that dry eye consists not only of ocular surface desiccation, but also of upregulation of the HLA-DR and ICAM-1 molecule in the conjunctival epithelium, possibly resulting in increased inflammation.

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Diagnosis of measles viral pneumonia in a patient with Hodgkin's disease by reverse transcription-polymerase chain reaction of serum

Mori Shigehisa, Maruyama Hiroshi, Ito Isao, Tokuhira Michihide, Koide Jun, Takeuchi Tsutomu, Itoyama Shinji, Masunaga Atsuko, Fukushima Masao, Suzuki Hiroshi, Abe Tohru

International Journal of Hematology 68 （ 3 ） 327 - 331 1998年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0925-5710

We report a case of fatal measles viral pneumonia in a patient with Hodgkin's disease who had no rash. The measles viral cDNA was detected in autopsy tissue from the lung by reverse transcription-polymerase chain reaction. This method was then applied successfully to stored serum. The diagnosis of measles viral pneumonia may be improved by the application of RT-PCR using peripheral blood. Sequence analysis of amplified cDNA suggested the virus infecting this patient was a recent strain, predominantly isolated after 1980. The fatal outcome may have been due to a lack of immune response to the newer strain.

Mutations in T cell receptor ζ chain mRNA of peripheral T cells from systemic lupus erythematosus patients

Tsuzaka Kensei, Takeuchi Tsutomu, Onoda Natsuko, Pang Ming, Tohru Abe

Journal of Autoimmunity 11 （ 5 ） 381 - 385 1998年10月

研究論文（学術雑誌）, 査読有り, ISSN 0896-8411

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of unknown aetiology. Although it has been reported that T cells might be responsible for the pathogenesis of SLE, it remains unclear whether immune aberrations of SLE T cells are the primary event in this pathological process. We have recently reported that tyrosine phosphorylation and expression of the T cell receptor zeta chain (TCR ζ) was significantly decreased in SLE T cells and that two SLE patients exhibited a 36 bp, exon 7 deletion of the TCR ζ mRNA. To investigate further common mutations in TCR ζ mRNA among SLE patients, mRNA was isolated from the peripheral blood T cells of two normal controls, two systemic sclerosis (SSc) patients, and eight SLE patients. TCR ζ cDNA was amplified by RT-PCR. Five out of the eight SLE patients exhibited abnormal migration patterns of the TCR ζ cDNA in PCR single stranded conformational polymorphism analysis. PCR products were ligated into pUC18 and five clones obtained were sequenced. Analysis of the nucleotide sequences revealed that all of the five pUC18 clones from the normal controls and SSc patients had the normal nucleotide sequence, whereas all eight SLE patients had mutations in TCR ζ cDNA accompanied by predicted amino acid substitutions. Mutations found in six of these patients corresponded to those of the third immunoreceptor tyrosine-based activation motif (ITAM) domain or the GTP/GDP binding site in TCR ζ. Thus, these mutations in TCR ζ mRNA could be responsible for the decreased expression of the TCR ζ protein in SLE T cells.

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Up-regulation of αEβ7, a novel integrin adhesion molecule, on T cells from systemic lupus erythematosus patients with specific epithelial involvement

Pang Ming, Abe Tohru, Fujihara Tsutomu, Mori Shigehisa, Tsuzaka Kensei, Amano Kouichi, Koide Jun, Takeuchi Tsutomu

Arthritis and Rheumatism 41 （ 8 ） 1456 - 1463 1998年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0004-3591

Objective. To determine the possible role of a novel integrin, αEβ7, in the pathogenesis of systemic lupus erythematosus (SLE). Methods. Expression of αEβ7 was examined on peripheral blood lymphocytes (PBL) from normal subjects (n = 25) and patients with SLE (n = 31), primary Sjogren's syndrome (n = 7), or polymyositis/dermatomyositis (n = 8) by cytofluorometry and/or immunoprecipitation. Adhesion of αEβ7+ T cells to HSG epithelial cells was investigated using a confocal image analyzer. Results. After phytohemagglutinin stimulation, expression of αEβ7 on PBL, especially on CD8+ T cells, was significantly higher in SLE patients than in normal subjects (P < 0.01). Elevated αEβ7 expression was associated with the presence of oral ulcers or serositis (P < 0.05). Activated SLE T cells with enhanced αEβ7 expression strongly adhered to HSG; this adhesion was partially blocked by anti-αEβ7. Conclusion. Expression and adhesion of αEβ7 on activated PBL was significantly increased in patients with SLE with epithelial involvement. This suggests a role of this novel integrin in tissue-specific retention of activated PBL, due to increased αEβ7-E- cadherin interaction, which may contribute to epithelial inflammation.

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TCR zeta chain lacking exon 7 in two patients with systemic lupus erythematosus

竹内勤

International Immunology 10 （ 7 ） 911 - 921 1998年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0953-8178

Decreased Fcγ receptor III (CD16) expression on peripheral blood mononuclear cells in patients with Sjogren's syndrome

Saito Keiko, Abe Tohru, Takeuchi Tsutomu

Journal of Rheumatology 25 （ 4 ） 689 - 696 1998年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

Objective. To examine the expression of surface structures important in natural killer (NK) cell function and the roles of serum factors affecting the expression of surface antigens on these cells in patients with Sjogren's syndrome (SS). Methods. Peripheral blood mononuclear cells (PBMC) of 18 patients with SS were analyzed by immunofluorescence on a flow cytometer. The antigen recognized by autoantibodies in their sera was analyzed by immunofluorescence and by immunoprecipitation. Results. Expression of Fcγ receptor III (CDI 6), an important indicator of NK cytolytic activity, on PBMC was significantly decreased in patients with SS who have extraglandular disease, while the expression of Fcγ RI and II was normal. Moreover, F(ab')₂ of IgG in these patients' sera was shown to bind to CD16+ cells. Immunoprecipitation study showed that it bound to CD16 itself. Conclusion. The depressed expression of CD16 on PBMC and the presence of antibody binding to CD16 in the patients' sera may be, at least in part, responsible for the altered function of NK cells observed in SS.

Lecithin-bound superoxide dismutase in the prevention of neutrophil- induced damage of corneal tissue

Matsumoto Koki, Shimmura Shigeto, Goto Eiki, Saito Keiko, Takeuchi Tsutomu, Miyajima Seiya, Negi Akira, Tsubota Kazuo

Investigative Ophthalmology and Visual Science 39 （ 1 ） 30 - 35 1998年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0146-0404

PURPOSE. To evaluate the effects of a lipophilic analog of superoxide dismutase (SOD) in the prevention of polymorphonuclear leukocyte (PMN)- induced damage to corneal epithelial cells in vitro and in bacterial corneal ulcers in vivo. METHODS. Immortalized human corneal epithelial cells (T- HCEC) were cocultured with human PMNs activated with N-formyl-methionyl- leucyl-phenylalanine for 18 hours, after which lactate dehydrogenase (LDH) activity of the supernatant was measured as a marker of cellular damage. The inhibitory effects of lecithin-bound SOD (PC-SOD) and unmodified SOD, as well as PMNs pretreated with anti-CD 18 monoclonal antibody, were compared with untreated control. The retention of each drug on the ocular surface of healthy volunteers was measured by flow cytometry using brush cytology samples. The protective effects of a 0.1% solution of PC-SOD on Pseudomonas aeruginosa corneal infection in guinea pigs were assessed by inflammatory grading scores and histology. RESULTS. Both PC-SOD and SOD effectively suppressed PMN-induced LDH release in T-HCEC in a dose-dependent manner. LDH release was also attenuated when PMNs were pretreated with anti-CD 18 antibodies, suggesting that adhesion molecules were involved in the process. Brush cytology of conjunctival samples showed that PC-SOD was retained longer on the ocular surface compared with unmodified SOD. PC-SOD significantly prevented excessive tissue damage by infiltrating PMNs in P. aeruginosa corneal infection, whereas in control eyes, perforation of the cornea occurred by 6 days. CONCLUSIONS. PC-SOD was effective in attenuating PMN- related tissue damage to corneal tissue both in vitro and in P. aeruginosa infection in guinea pigs.

TCR ζ chain lacking exon 7 in two patients with systemic lupus erythematosus

Takeuchi Tsutomu, Tsuzaka Kensei, Pang Ming, Amano Kouichi, Koide Jun, Abe Tohru

International Immunology 10 （ 7 ） 911 - 921 1998年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0953-8178

To address the molecular mechanism underlying the functional defects of peripheral T cells in systemic lupus erythematosus (SLE), we focused on early signaling events. We demonstrated that protein expression of the TCR ζ chain was significantly decreased in peripheral T cells from patients with SLE compared to normal controls and patients with systemic sclerosis (SSc). Among those patients showing decreased TCR ζ chain expression, we found two patients with pronounced TCR ζ chain abnormalities, including an aberrant 14 kDa form in one and only trace expression in the other. RT-PCR, SSCP and subsequent cloning of the transcripts revealed that bases 468-503, corresponding to exon 7, were deleted in both patients. Since exon 7 spans the GTP/GDP binding site and N-terminal tyrosine in the third ITAM domain of TCR ζ chain, the transcript lacking exon 7 may be responsible for altered signal transduction via TCR in these SLE patients.

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Respiratory syncytial virus-induced interleukin-4 production by human conjunctival epithelial cells contributes to allergy

Fujishima Hiroshi, Saito Ichiro, Okamoto Yoshitaka, Takeuchi Tsutomu, Tsubota Kazuo

Current Eye Research 17 （ 6 ） 656 - 662 1998年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0271-3683

Purpose. We previously reported allergic conjunctivitis was associated with a local pattern of cytokines and identified respiratory syncytial virus (RSV) in the conjunctival epithelium, in patients with allergic conjunctivitis. We hypothesized that RSV infected the normal conjunctival epithelium and produced interleukin-4 (IL-4), causing an allergic reaction. To determine this event, we studied production of IL-4 by human conjunctival epithelial cells, after infection with RSV. Methods. Conjunctival samples were collected with a special brush and were challenged with 5 x 10⁶ pfu/ml of live RSV. RSV infection was detected by immunocytochemical study and RT-PCR. HLA-DR antigen was expressed by flow cytometry. IL-4 was assayed by a sandwich ELISA. Results. Immunocytochemical study and RT-PCR showed that RSV infected the conjunctival epithelial cells. HLA-DR was demonstrated in the RSV-infected conjunctival epithelial cells. Average concentrations of IL-4 in culture supernatants in infected cells were 3.8 ± 1.8, 3.6 ± 1.1, and 5.4 ± 1.8 pg/ml at 24, 48, and 72 h, respectively. Levels in non-infected cells were 0.33 ± 0.0, 0.59 ± 0.69, and 0.4 ± 0.22 pg/ml, respectively (p > 0.001). Conclusion. Findings suggest that the expression of IL-4 is associated with intracellular infection by RSV in conjunctiva. With our former reports, RSV infection in conjunctival epithelial cells can be suggested as one of the possible environmental pathogens of allergic conjunctivitis.

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Lacrimation and salivation are not related to lymphocytic infiltration in lacrimal and salivary glands in MRL lpr/lpr mice

Fujita Hiromi, Fujihara Tsutomu, Takeuchi Tsutomu, Saito Ichiro, Tsubota Kazuo

Advances in Experimental Medicine and Biology 438 941 - 948 1998年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0065-2598

Granulomatous amoebic encephalitis caused by Acanthamoeba in a patient with systemic lupus erythematosus

Koide J., Okusawa E., Ito T., Mori S., Takeuchi T., Itoyama S., Abe T.

Clinical Rheumatology 17 （ 4 ） 329 - 332 1998年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0770-3198

A 25-year-old chronically immunosuppressed woman with systemic lupus erythematosus (SLE) died after developing subacute granulomatous encephalitis caused by Acanthamoeba. Amoebic trophozoites were also found in the lung, suggesting a primary pulmonary focus of infection. The infectious encephalitis was difficult to differentiate from a flare-up of central nervous system lupus. This case illustrates that Acanthamoeba can cause fatal encephalitis in lupus patients, as well as in patients with acquired immunodeficiency syndrome as previously reported. To our knowledge, this is the first reported case of granulomatous amoebic encephalitis due to Acanthamoeba in a patient with SLE.

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Serum soluble Fas/APO-1 is increased in patients with primary Sjogren's syndrome

Fujihara T., Takeuchi T., Tsubota K., Kayagaki N., Yagita H., Okumura K., Abe T.

Clinical Rheumatology 17 （ 6 ） 496 - 499 1998年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0770-3198

The aim of the study was to elucidate the involvement of Fas antigen in human autoimmune disease, by analysing serum levels of soluble Fas/APO1 protein in patients with various autoimmune diseases, including system lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM), Behcet's syndrome and Sjogren's syndrome (SjS). The levels of soluble Fas/APO-1 in sera were quantitated by a sandwich enzyme-linked immunosorbent assay. Soluble Fas/APO-1 levels were significantly increased in serum from patients with primary Sjogren's syndrome (1°SjS) compared with control subjects. However, no significant differences in soluble Fas/APO-1 levels were noted in patients with secondary Sjogren's syndrome (2°SjS) nor in patients with any of the other autoimmune diseases. The soluble Fas/APO-1 level in 1°SjS patients with extraglandular diseases was significantly higher than that in patients without extraglandular diseases. These results suggest that soluble Fas/APO-1 protein may play an important role in the pathogenesis of 1°SS.

Reduced protein tyrosine phosphatase (PTPase) activity of CD45 on peripheral blood lymphocytes in patients with systemic lupus erythematosus (SLE)

竹内勤

Clinical and Experimental Immunology 109 （ 1 ） 20 - 26 1997年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0009-9104

Soluble interleukin-2 receptors and serum autoantibodies in dry eye patients

Tsubota Kazuo, Fujihara Tsutomu, Takeuchi Tsutomu

Cornea 16 （ 3 ） 339 - 344 1997年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0277-3740

Purpose. Sjogren's syndrome (SS) is a systemic autoimmune disease characterized by decreased lacrimal and salivary gland function causing dry eye and dry mouth. We examined several parameters as measures of lacrimal function and compared the serum soluble interleukin-2 receptor (sIL-2R) and serum autoantibodies as measures of systemic autoimmune condition. Methods. Serum levels of sIL-2R, antinuclear antibody (ANA), and rheumatoid factor (RF), in 128 patients (16 men, 112 women; average age, 54.3±12.5 years) were measured. The lacrimal function was evaluated clinically. Results. There was no correlation between systemic condition and the cotton-thread test, Schirmer test with or without anesthesia, tear clearance test, tear-function index, or the BUT. However, the Schirmer test with nasal stimulation and rose bengal and fluorescein staining was positively correlated with systemic parameters. Conclusion. We show the correlation of serum sIL-2R, ANA, and RF to lacrimal function, which is good evidence that systemic immune conditions directly affect local lacrimal gland function.

Flow cytometric analysis of surface antigens on human conjunctival epithelial cells

Fujihara Tsutomu, Takeuchi Tsutomu, Saito Keiko, Tsubota Kazuo

Ophthalmic Research 29 （ 2 ） 103 - 109 1997年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0030-3747

We analyzed the levels of expression of different surface adhesion molecules on normal human conjunctival epithelial cells with cytology and flow cytometry. The levels of β₁ (CD29), VLA-1 (CD49a), VLA-2 (CD49b), and VLA-3 (CD49c) integrins were high, whereas those of VLA-5 (CD49e) and VLA-6 (CD49f) were faint, and that of VLA-4 (CD49d) was undetectable. Among the β₂ integrins, the levels of Mac-1 (CD11b) and p150.25 (CD11c) were positive, while LFA-1 (CD11a) was not detectable. HLA class I and class II were also expressed. However, CR2 (CD21), CD57, CD44 and ICAM-1 (CD54) were not detected. Our study suggests that these techniques may aid in identifying changes in the expression levels of various surface antigens on conjunctival epithelial cells that could occur in ocular surface disease.

Spontaneous establishment of an Epstein-Barr virus-infected fibroblast line from the synovial tissue of a rheumatoid arthritis patient

竹内勤

Journal of Virology 71 （ 3 ） 2478 - 2481 1997年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0022-538X

Flow cytometric analysis of surface antigens on human conjunctival epithelial cells

竹内勤

Ophthalmic research 29 （ 2 ） 103 - 109 1997年01月

研究論文（学術雑誌）, 共著, ISSN 0030-3747

Elevated levels of substance P in tears of patients with allergic conjunctivitis and vernal keratoconjunctivitis

Fujishima H., Takeyama M., Takeuchi T., Saito I., Tsubota K.

Clinical and Experimental Allergy 27 （ 4 ） 372 - 378 1997年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0954-7894

Background - Recent studies have suggested that the nervous system may participate in inflammatory processes. Substance P (SP) acts as a chemical mediator as well as a neurotransmitter. Objective - In order to clarify the pathogenesis of ocular allergic diseases, we assessed the concentration of SP in tears. Methods - Using a highly sensitive and specific double-antibody enzyme immunoassay (EIA), we determined the SP concentration in tears of 10 patients with seasonal allergic conjunctivitis, 10 with atopic dermatitis without keratoconjunctivitis (AD), 13 with vernal keratoconjunctivitis (VKC) and 65 normal controls. Giemsa's staining for brush cytology samples and histocytological study by immunocytochemical staining of giant papillary conjunctival cells from VKC and normal controls was conducted. Results - The mean SP level was low in the normal controls anti AD, whereas patients with seasonal allergic conjunctivitis and VKC showed significant elevation of SP (P < 0.01). Brush cytology samples showed conjunctival epithelial cells with lymphocytes, neutrophils and eosinophils that were not seen in normal subjects. Histocytological examination demonstrated SP positive cells in the conjunctiva of patients with VKC, but not in normal controls. Conclusion - This study suggests that the increased level of SP in tears may contribute to the pathogenesis and severity of ocular allergic diseases.

Characterization of cytokine mRNA transcripts in conjunctival cells in patients with allergic conjunctivitis

Fujishima Hiroshi, Saito Ichiro, Takeuchi Tsutomu, Shinozaki Naoshi, Tsubota Kazuo

Investigative Ophthalmology and Visual Science 38 （ 7 ） 1350 - 1357 1997年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0146-0404

Purpose. The host response to allergens appears to be regulated by specific patterns of local cytokine production. More than 20,000 conjunctival superficial cells were collected with a special brush, a smaller version of the Cytobrush used in cervical cytology, from the upper palpebral conjunctiva. Methods. Samples were obtained by cytology brush from seven patients with allergic conjunctivitis and from seven healthy volunteers. Giemsa staining, immunocytochemistry, and flow cytometric analysis were performed. Cytokine gene expression was assayed by the reverse- transcription-polymerase chain reaction method. Results. Giemsa staining of cytocentrifuged preparations from patients with allergic conjunctivitis showed conjunctival epithelial cells with lymphocytes, mast cells, and eosinophils. In an immunohistochemically study, a few CD3- and CD4- bearing cells, but not CD20- and CD14- bearing cells, were seen in patients. In 82.6 ± 17% of the samples obtained from allergic patients, HLA-DR was present, but it was present in only 34.2 ± 17.8% of samples from control subjects (P = 0.0001) using flow cytometric analysis. Steady state transcripts of mRNA for cytokines were analyzed with RT-PCR in conjunctival cell samples, and results showed that samples from allergic conjunctivitis expressed increased transcripts of interleukin 4 and interleukin 13 but virtually no interleukin 2 or interferon-γ; six samples from seven healthy subjects expressed no interleukin 2, interleukin 4, interleukin 13, or interferon-γ transcripts. Conclusions. These results suggest that the clinical features of allergic conjunctivitis in humans are associated with a specific local pattern of proinflammatory cytokine expression.

Evaluation of human conjunctival epithelium by a combination of brush cytology and flow cytometry

Fujihara Tsutomu, Takeuchi Tsutomu, Saito Keiko, Kitajima Yasuo, Kobayashi Tadao K., Tsubota Kazuo

Diagnostic Cytopathology 17 （ 6 ） 456 - 460 1997年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 8755-1039

Cytology using the brush technique is readily available and is a rapid means of establishing a presumptive diagnosis of ocular surface changes. However, those techniques have some limitations when obtaining cells from certain localized areas particularly if using the Cytobrush-S®. We have described here a new type of brush (Accellon-M®), which can collect the local cells using its spherical tip, and evaluated them by comparing with Cytobrush-S®. Furthermore, we differentiated epithelial cells from non- epithelial cells that were collected by brushing, and by a combination of brush cytology and flow cytometry using an anti-keratin antibody, AE-3, which reacts with all basic epithelial keratins. Accellon-M® could collect the epithelial cells from conjunctiva as effectively as with the Cytobrush-S®, and there were no statistical differences between both groups. AE-3, which is reported as the marker of epithelial cells, were detected quantitatively by a combination of brush cytology and flow cytometry techniques. The result of the present study emphasizes that both the Cytobrush-S® and the Accellon- M® are valuable for conjunctival brush cytology. An additional positive feature of the Accellon-M® may be improved cell collection from the conjunctival epithelium especially when the target cells are in a limited area. The combination of the brush cytology and the flow cytometry technique appears to be a useful adjunct as an additional diagnostic or research tool for use in the detection of various antigens in the conjunctival epithelium.

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Lacrimation and salivanon is not relatedtothe cd4 positive lymphoctteinfiltration in lacrimaland salivary gland in

Fujihara T., Takeuchi T., Saito I., Tsubota K.

Investigative Ophthalmology and Visual Science 38 （ 4 ） 1997年

研究論文（国際会議プロシーディングス）, 共著, 査読有り, ISSN 0146-0404

Purpose: We measured the secretion volume of tear and sauva in MRL and BALB/c mice to confirm that lacrimationand salivation is related to lymphocyte infiltration in these glands. Methods: To quantify the tear secretion volume. Schirmer test with cotton thread test was performed in MRL/ipr, MRL/+ and BALB/c mice. Saliva secretion volume was measured with capillary tube. Lymphocytic infiltration into the exocrine glands was graded, and infiltrated lymphocytes were characterized by immunohislochemistry. The apoptotic cells in the exocrine glands were detected by TUNEL method. Results: There were no significant differences in tear secretion between BALB/c and MRL/lpr or MRL/+ mice. In MRL/lpr the saliva secretion was reduced in the comparison with BALB/c mice. Immunohistochemical analysis revealed that the CD4 positive T lymphocytes were located in the focus region in both of the glands in MRL/lpr and MRL/+ mice. In the salivary gland, the CDS positive T lymphocytes were observed in the focus region and around acini and duct in MRL/lpr mice. In the salivary glands the apoptotic cells were detected at the ductal and acinar cells only in MRL/lpr mice. Conclusion: In this study, we found that the CD4 positive T lymphocyte dose not necessarily result in the decrease of the secretion. In salivary gland. CDS positive lymphocytes around acini and duct may cause the apoptosis of the acinar and ductal epithelial ceils and the dysfunction of the salivary secretion.

Interleukin-4 and IgE in seasonal allergic conjunctivitis

Fujishima Hiroshi, Shimazaki Jun, Takeuchi Tsutomu, Saito Ichiro, Tsubota Kazuo

Ophthalmologica 210 （ 6 ） 325 - 328 1996年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0030-3755

We measured interleukin-4 (IL-4) and IgE to study their presence in patients with seasonal allergic conjunctivitis. Twenty patients and 10 normal subjects were enrolled in this study, and their brush cytology samples and peripheral blood lymphocytes (PBL) were cultured for 3 or 24 h. IL-4 levels were measured using ELISA in the supernatants. Measurements of serum IgE were also performed. IL-4 was detected in 4 of 40 brush cytology samples and 10 of 40 PBL samples, but not from the controls. IL-4 positivity rate of patients was significantly higher than normal in 24-hour cultured PBL (p = 0.03). Patients' serum IgE was also significantly higher (p = 0.006). IL-4 may contribute to the development of seasonal allergic conjunctivitis.

Measurement of interleukin-4 and histamine in superficial cells of conjunctiva in patients with allergic conjunctivitis

竹内勤

Current Eye Research 15 （ 2 ） 209 - 213 1996年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0271-3683

Signal transduction through CD16 in human conjunctival epithelial cells

竹内勤

Investigative Ophthalmology and Visual Science 37 （ 3 ） 1653 - 1653 1996年02月

研究論文（国際会議プロシーディングス）, 共著, 査読有り, ISSN 0146-0404

Interleukin-4 and IgE in seasonal allergic conjunctivitis

竹内勤

Ophthalmologica 210 （ 6 ） 325 - 328 1996年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0030-3755

Biopsy of labial salivary glands and lacrimal glands in the diagnosis of sjögren's syndrome

Xu Ke Ping, Katagiri Shigeo, Takeuchi Tsutomu, Tsubota Kazuo

Journal of Rheumatology 23 （ 1 ） 76 - 82 1996年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

Objective. To determine the diagnostic value in Sjögren's syndrome (SS) of evaluating the presence of focal adenitis in labial salivary gland (LSG) and lacrimal gland (LG) biopsy specimens. Methods. We studied 105 cases with suspected SS and performed biopsies prospectively. The diagnostic criteria of Fox, et al were followed. The Chisholm-Mason grading standard and Greenspan focus score were used for evaluation. Results. Epimyoepithelial islands and severe lymphocyte infiltration with germinal centers were observed only in LG biopsy specimens (5.9 and 3.5%, respectively). The lymphocytic focus scores of LG (2.5 ± 2.1/4 mm²) were significantly higher than those of LSG specimens (1.3 ± 1.1/4 mm²) in 23 cases with both biopsy results (p < 0.05). Six of the 32 LSG biopsies were normal while their LG biopsies were significantly higher. Conversely, 5 of the 32 LG biopsies were aided by corresponding LSG biopsies, since in LG biopsies no glandular tissue was obtained. Evaluation of both specimens for the same patient was significantly more effective in diagnosing SS than using either specimen alone (p < 0.01). Conclusion. LG biopsy specimens have a more evident histopathology than LSG biopsy specimens. We recommend that both LSG and LG biopsies be performed in patients with suspected SS to reduce false negative results and improve diagnostic accuracy.

Decreased reflex tearing is associated with lymphocytic infiltration in lacrimal glands

Tsubota Kazuo, Xu Ke Ping, Fujihara Tsutomu, Katagiri Shigeo, Takeuchi Tsutomu

Journal of Rheumatology 23 （ 2 ） 313 - 320 1996年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

Objective. To investigate whether reflex tearing measured by the Schirmer test with nasal stimulation is better correlated with lymphocytic infiltration of the lacrimal gland and is thus a more appropriate test for Sjogren's syndrome (SS). Methods. 272 patients with dry eye (age 55.5 ± 13.5 years) with regular Schirmer test results <10 mm were recruited for the study. They were divided into 2 groups depending on the results of the Schirmer test with nasal stimulation. 24 age and sex matched patients from each group were selected for lacrimal gland biopsy and 10 patients for salivary gland biopsy, and the levels of systemic autoantibodies and degrees of ocular surface staining and lymphocytic infiltration of the lacrimal and salivary glands were compared. Results. Of the 272 patients, 187 (68.8%) had good reflex tearing (GT) and 85 (31.2%) had poor reflex tearing (PT). There were no significant differences in the age or sex of the 2 groups. Lymphocytic infiltration of the lacrimal gland was observed in 7 GT cases and 22 PT cases out of 24 cases. Lymphocytic infiltration of the salivary gland was also higher in the PT (6 of 10) than the GT group (2 of 10). Conclusion. Evaluation of reflex tearing by the Schirmer test with nasal stimulation identifies 2 groups of patients with dry eye. Those with poor reflex tearing were more likely to have autoantibodies and lymphocytic infiltration of the exocrine glands consistent with SS.

SYSTEMIC LUPUS-ERYTHEMATOSUS WITH NECROTIZING VASCULITIS AND UP-REGULATED EXPRESSION OF VLA-4 ANTIGEN

竹内勤

Clinical Rheumatology 14 （ 3 ） 370 - 374 1995年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0770-3198

Systemic lupus erythematosus with necrotizing vasculitis and upregulated expression of VLA-4 antigen

Takeuchi T., Aoki K., Koide J., Sekine H., Abe T.

Clinical Rheumatology 14 （ 3 ） 370 - 374 1995年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0770-3198

We report on a patient (S.A.), with well-defind SLE who developed a perforation of the ileum due to pathologically confirmed necrotizing vasculitis. No anti-DNA antibody was detected at the ileal perforation, and the serum complement level was normal. These findings rais ethe alternative possibility of a cellmediated immune mechanism as a cause of necrotizing vaculitis. Upregulateed expression and function of VLA-4 antigen on peripheral blood T cells were oberved, suggesting that T cells with VLA-4 antigen may participate in the onset and/or perpetuation of vascular inflammation. © 1995 Acta Medica Belgica.

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Measurement of IL-4 in tears of patients with seasonal allergic conjunctivitis and vernal keratoconjunctivitis

Fujishima H., Takeuchi T., Shinozaki N., Saito I., Tsubota K.

Clinical and Experimental Immunology 102 （ 2 ） 395 - 398 1995年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0009-9104

To elucidate the mechanism of ocular surface allergic disease, we focused on IL-4, which is one of the key factors in regulating IgE production, and thus determined the concentration of IL-4 in tears. IL-4 concentration was determined in the tears of 15 patients with seasonal allergic conjunctivitis, 15 vernal keratoconjunctivitis (VKC), 10 giant papillary conjunctivitis (GPC), 10 patients with non-allergic conjunctivitis and post-cataract surgical conjunctivitis as intermediate conjunctivitis, and 10 normal subjects using a highly sensitive sandwich ELISA. The mean level of IL-4 in normal controls was low, and seasonal allergic conjunctivitis, VKC and GPC showed a significant elevation (P < 0.05), respectively. IL-4 of VKC and GPC were also significantly higher than allergic conjunctivitis, and non-allergic conjunctivitis and post-cataract surgical conjunctivitis were not higher than normal. These results raise the possibility that the increased level of IL-4 in tears could play a role in allergic disease and its severity in patients.

An unusual variant of Wegener's granulomatosis and the role of integrin adhesion receptors for pulmonary lesion

Amano K., Sekine H., Itoh T., Hosono O., Koide J., Takeuchi T., Abe T.

Japanese Journal of Rheumatology 5 （ 3 ） 217 - 226 1994年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0169-1163

We report a patient with Wegener's granulomatosis (WC) whose initial manifestation was acute renal failure. The open renal biopsy specimen revealed periglomerular granulomatosis with crescentic glomerulonephritis. Pulmonary lesion appeared late period of his illness. Both renal and pulmonary disease responded to prednisolone and cyclophosphamide treatment. Serial determination of adhesive receptors on the patient's peripheral blood lymphocytes showed upregulated expression and function when his pulmonary lesion had appeared and returned to normal when the pulmonary lesion subsided. We think that the patient represents an unusual variant of WG and discuss the role of upregulated adhesive receptors for the development of the pulmonary lesion.

Upregulated expression and function of integrin adhesive receptors in systemic lupus erythematosus patients with vasculitis

Takeuchi Tsutomu, Amano Kouichi, Sekine Hiromi, Koide Jun, Abe Tohru

Journal of Clinical Investigation 92 （ 6 ） 3008 - 3016 1993年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0021-9738

Upregulation of integrin adhesive receptors has been implicated in various pathological conditions. We examined expression and function of integrin adhesive receptors on peripheral blood lymphocytes from patients with systemic lupus erythematosus (SLE), particularly those with the complication of vasculitis, and found that VLA-4 and LFA-1 expression was increased in SLE patients with vasculitis, while LFA-1 but not VLA-4 expression was increased in those without vasculitis. These results suggested a role of VLA-4 in the pathogenesis of vasculitis in SLE. Functional studies further demonstrated that adhesion to cytokine-activated human umbilical cord vein endothelial cells and to the CS-1 alternatively spliced domain of fibronectin was significantly increased in SLE patients with vasculitis. Analysis of the functional epitopes on the α₄ chain demonstrated that antigen densities of all the functional epitopes were increased in those with vasculitis, indicating that the increased expression of VLA-4 resulted from the increased number of VLA-4 molecules, and was not secondary to an increase in one particular functional epitope. Immunoprecipitation studies further support these results. Interestingly, high molecular weight bands associated with VLA-4 were observed in about half of the SLE patients with vasculitis. These results introduce a possibility that upregulation of integrin adhesive receptors has a potential role in the pathogenesis of vasculitis in SLE.

Integrin VLA-5 negative primary plasma cell leukemia.

Ohtake K., Takeuchi T., Saito K., Ito T., Ito I., Aoki K., Takano Y., Amano K., Hosono O., Koide J.

Internal medicine (Tokyo, Japan) 32 （ 7 ） 565 - 568 1993年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0918-2918

We present a case of primary plasma cell leukemia with Bence Jones proteinuria. After combination chemotherapy, leukemic cells and the urinary levels Bence Jones protein were decreased. Small lytic bone lesions were detected only in the skull. Typical plasma cells were rarely seen in peripheral blood on the hyperleukocytic phase, however they were increased in the advanced stages. The most important diagnostic sign was persistent expression of CD38 antigen on leukemic cells throughout the entire course of the illness and these leukemic cells expressed very late antigen-4 (VLA-4) but not VLA-5.

Expression of cell adhesion molecules in the salivary and lacrimal glands of Sjogren's syndrome

Saito I., Terauchi K., Shimuta M., Nishiimura S., Yoshino K., Takeuchi T., Tsubota K., Miyasaka N.

Journal of Clinical Laboratory Analysis 7 （ 3 ） 180 - 187 1993年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0887-8013

We attempted to determine whether cell adhesion molecules, including vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule- 1 (ICAM-1), and E-selectin (endothelial-leukocyte adhesion molecule-1; ELAM- 1), are involved in the lymphoid cell infiltration of the salivary and lacrimal glands in Sjogren's syndrome (SS) patients. Both immunohistochemical analysis and the reverse-transcripts polymerase chain reaction (RT-PCR) were used to analyze the expression of VCAM-1, ICAM-1, ELAM-1, very late antigen 4 (VLA-4 [α4, β1]), lymphocyte function-associated antigen-1 (LFA-1), interferon-γ(IFN-γ), tumor necrosis factor (TNF), and interleukin-1 β (IL- 1β). Immunohistochemical analysis of salivary gland biopsies from SS patients showed a marked expression of VCAM-1 and ICAM-1 in the venules surrounded by infiltrated CD4⁺ CD45RO⁺ T cells. E-selectin was expressed on vascular endothelium with weak intensity. Increased levels of VCAM-1, ICAM- 1, IFN-γ, and IL-1β mRNA were demonstrated by RT-PCR, whereas E-selectin mRNA were weakly expressed in SS lacrimal and salivary gland tissues. This is in contrast with strong expression of ELAM-1 in IL-1β-stimulated human umbilical vascular endothelial cells (HUVEC) in vitro. Cytokine-mediated up- regulation of VCAM-1 and ICAM-1 that facilitates the recruitment of VLA-4 and LFA-1 expressing T cells might contribute to lymphoid cell infiltration in the salivary and lacrimal glands in SS.

EXPRESSION OF CELL-ADHESION MOLECULES IN THE SALIVARY AND LACRIMAL GLANDS OF SJOGRENS-SYNDROME

竹内勤

Journal of Clinical Laboratory Analysis 7 （ 3 ） 180 - 187 1993年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0887-8013

The presence of anti-protein A antibodies in patients with rheumatoid arthritis

Takeuchi T., Hosono O., Koide J., Amano K., Sekine H., Abe T.

Scandinavian Journal of Immunology 33 （ 5 ） 585 - 592 1991年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0300-9475

Sixteen patients with rheumatoid arthritis (RA) were examined for the presence of anti-protein A antibodies. The F(ab')₂ preparations from five RA patients showed significant binding to IgG-free protein A on ELISA. The protein A binding was further examined by immunoblotting. The F(ab')₂ preparations of high protein A-binding protein gave a specific reaction with IgG-free protein A on nitrocellulose paper. This demonstrates the presence of anti-protein A antibodies in patients with RA. Those RA patients with anti-protein A antibodies had more active disease as judged by the Lansbury's activity index. The level of serum rheumatoid factor (RAHA) was significantly higher in patients with anti-protein A antibodies than in those without anti-protein A antibodies.

Thrombotic thrombocytopenic purpura in two patients with systemic lupus erythematosus

Itoh Yoshihiro, Sekine Hiromi, Hosono Osamu, Takeuchi Tsutomu, Koide Jun, Takano Makoto, Abe Tohru

Clinical Immunology and Immunopathology 57 （ 1 ） 125 - 136 1990年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0090-1229

Thrombotic thrombocytopenic purpura (TTP) is a clinical syndrome of unknown etiology and has a high mortality rate due to disseminated platelet thrombi. However, the mechanism of platelet agglutination is not understood. Although an immunological mechanism has been suggested as the basis for the pathogenesis of TTP, any possible immunemediated etiology remains unclear. The association of TTP with systemic lupus erythematosus (SLE) affords a unique opportunity to study such possibilities, because SLE is a prototype of autoimmune disease. This report describes two patients with SLE who developed TTP. The development of anti-platelet antibodies is one possible immunological mechanism for platelet agglutination in patients with SLE complicated by TTP. More importantly, patient J.Y., who had anti-platelet antibodies, responded dramatically to high doses of prednisolone. © 1990.

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CCA [N-(2-carboxyphenyl)-4-Chloroanthranilic acid disodium salt], a newly developed immunomodulating drug, suppresses T-cell activation by acting on macrophages

Takeuchi Tsutomu, Koide Jun, Hosono Osamu, Takano Makoto, Abe Tohru

Inflammation 13 （ 2 ） 125 - 135 1989年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0360-3997

The cellular mechanism of action of a newly developed drug, CCA, N-(2-carboxyphenyl)-4-chloroanthranilic acid disodium salt, on PHA-, autologous mixed lymphocyte reaction (AMLR)-, and phorbol myristate acetate (PMA)-stimulated T-cell proliferation was investigated. Addition of 50 μg of CCA per milliliter suppressed PHA- and AMLR-stimulaled T-cell proliferation. In contrast. CCA failed to suppress PMA-stimulated macrophage-depleted T-cell proliferation. After treatment of T cells or macrophages with CCA for 12 h, recombined T cells and macrophages were stimulated with phytohemagglutinin. [³H]Thymidine incorporation by T cells was suppressed when macrophages but not T cells were treated with CCA. These results indicate that CCA suppresses T-cell proliferation by acting on macrophages. The mechanism involved in this suppression of CCA was due to the loss of Ia antigen on macrophages and the loss of interleukin-1 (IL-1) secretion from macrophages. © 1989 Plenum Publishing Corporation.

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Functional characterization of the CD45R (2H4) molecule on CD8 (T8) cells in the autologous mixed lymphocyte reaction system

Takeuchi T., Rudd C. E., Tanaka S., Rothstein D. M., Schlossman S. F., Morimoto C.

European Journal of Immunology 19 （ 4 ） 747 - 755 1989年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0014-2980

In the present study, we have investigated the molecular basis for the immunoregulatory function of CD8 cells after autologous mixed lymphocyte reaction (AMLR) activation. We demonstrated that the CD8⁺CD45R⁺, but not the CD8⁺CD45R^- subset of cells effected suppression following AMLR activation. In contrast, cytotoxic activity against alloantigens resided in both the CD8⁺CD45R⁺ and CD8⁺CD45R^- subsets of cells. Biochemical analysis showed that on CD8 cells, the 220-kDa isoform of the LCA/T200 antigen family was better represented than the 200-kDa isoform, when compared to CD4 cells. The density of the CD45R antigen increased on CD8 cells following activation in AMLR and treatment of AMLR-activated CD8 cells with either anti-CD45R antibody or anti-CD3 antibody abolished the suppressor function of these cells. In contrast, treatment of AMLR-activated CD4 cells with anti-CD45R, but not anti-CD3 antibody, abolished the suppressor/inducer function of these cells. The results suggest that the CD45R antigen as well as CD3 T cell receptor complex have an important role in the suppressor function of AMLR-activated CD8 cells.

Amplification of suppressor inducer pathway with monoclonal antibody, anti-2H4, identifying a novel epitope of the common leukocyte antigen/T200 antigen

Takeuchi Tsutomu, Rudd Christopher E., Tedder Thomas F., Schlossman Stuart F., Morimoto Chikao

Cellular Immunology 118 （ 1 ） 68 - 84 1989年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0008-8749

The 2H4 antigen, comprised of a 200 220-kDa glycoprotein of the leukocyte common antigen (LCA) family, is expressed on a suppressor inducer, but not a helper inducer subset of T4 cells. Earlier studies have demonstrated that the T4+2H4+ subset of cells maximally responded to the AMLR and this molecule had an important role in generated suppressor signals in AMLR/ Con A-activated T cell systems. In the present study, we examined the effect of a series of monoclonal antibodies including anti-2H4 antibody on the initial activation of T4 cells in response to self-Ia antigens. We found that the addition of anti-2H4 antibody resulted in an augmentation of the proliferative response of T4 cells in AMLR, whereas other antibodies reactive with LCA/ T200 antigens lacked this ability. Furthermore, anti-2H4 antibody enhanced both IL-2 production and IL-2R expression in this AMLR system. This enhancing effect was inhibited by anti-T3 antibody. Moreover, the suppressor inducer function of AMLR T4 cells was enhanced with anti-2H4 antibody by increasing the number of 2H4+ cells with high antigen density. Taken together, these results suggest that the 2H4 antigen may serve as an accessory structure for enhancing the activation of the T4+2H4+ suppressor inducer subset at initiation of cell triggering. © 1989.

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Cellular regulation of anti-nRNP antibody synthesis is different from that of anti-DNA antibody synthesis in patients with systemic lupus erythematosus

Hosono O., Takeuchi T., Koide J., Takano M., Abe T.

Rheumatology International 8 （ 4 ） 177 - 183 1988年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0172-8172

The cellular regulation of anti-nuclear ribonucleoprotein (nRNP) antibody synthesis in patients with systemic lupus erythematosus (SLE) was examined and compared with that of anti-double-stranded DNA (dsDNA) antibodies. In vitro antibody production by lymphocytes from SLE patients with antibodies to either dsDNA or nRNP alone was measured using dsDNA-specific and nRNP-specific solid-phase radioimmunoassays (RIA). Lymphocytes of SLE patients with only anti-dsDNA antibodies and normal individuals failed to synthesize anti-nRNP antibody with or without nRNP stimulation. In contrast, lymphocytes from SLE patients with anti-nRNP antibody alone in their sera synthesized in vitro a large amount of anti-nRNP antibody with or without nRNP stimulation. Experiments with reconstituted autologous lymphocytes indicated that B cells and T cells were required for anti-nRNP antibody synthesis. As expected, helper function for antibody synthesis by autologous B cells resided in the T4-cell population and suppressor function in the T8-cell population. T8 cells from SLE patients with anti-nRNP antibody alone suppressed anti-nRNP antibody synthesis by autologous B cells irrespective of clinical activity. This is in contrast to anti-dsDNA antibody production, which was not suppressed by autologous T8 cells. These results indicate that the cellular regulation of anti-nRNP antibody synthesis in SLE is different from that of anti-dsDNA antibody syntheis. Increased anti-nRNP antibody synthesis may be due to increased T4-helper cell function rather than defective T8-suppressor function. © 1988 Springer-Verlag.

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CD11 molecule defines two types of suppressor cells within the T8⁺ population

Takeuchi Tsutomu, DiMaggio Marjorie, Levine Herbert, Schlossman Stuart F., Morimoto Chikao

Cellular Immunology 111 （ 2 ） 398 - 409 1988年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0008-8749

It has been shown that T8⁺ cells are comprised of functionally heterogeneous subpopulations such as suppressor, cytotoxic, and NK cells. In this report, we attempted to delineate the functional heterogeneity of T8 cells defined by anti-CD11 antibody (anti-Mol). Although allospecific cytotoxic activity was restricted to the T8⁺Mol^- subset, suppression of PWM IgG synthesis could be elicited in both the T8⁺Mol⁺ and the T8⁺Mol^- subset of cells. However, the mechanism of suppression was different in these two subsets. Suppression by the T8⁺Mol^- subset of cells required the interaction with the T4⁺2H4⁺ suppressor inducer cells, whereas the T8⁺Mol⁺ subset of cells could suppress in the absence of the suppressor inducer cells. Moreover, recombinant interleukin-2 alone could augment this suppression by the T8⁺Mol⁺ subset, but did not induce suppression by the T8⁺Mol^- subset. In contrast, NK and LAK activity was exclusively found in the T8⁺Mol⁺ subset of cells but not in the T8⁺Mol^- subset of cells. These results suggest that the CD11 molecule is useful for distinguishing novel subsets of T8 cells. © 1988.

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Suppression of in vitro production of anti-U1-ribonucleoprotein antibody by monoclonal anti-idiotypic antibody to anti-U1-ribonucleoprotein antibody

Koide J., Takeuchi T., Hosono O., Takano M., Abe T.

Scandinavian Journal of Immunology 28 （ 6 ） 687 - 696 1988年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0300-9475

We produced monoclonal anti-idiotypic antibody against immunoaffinity purified anti-U1-ribonucleoprotein (RNP) antibody from a patient (K.T.), by the cell fusion procedure. The specificity of monoclonal anti-idiotypic antibody (IgG1, κ) was determined by inhibition studies. With the monoclonal anti-idiotypic antibody, cross-reactive idiotypes on anti-U1-RNP antibodies from unrelated patients with anti-U1-RNP antibody was detected in 57% of the samples. The anti-idiotypic antibody specifically suppressed the in vitro production of anti-U1-RNP antibody by lymphocytes from the patient K.T., and unrelated patients with a cross-reactive idiotype, in whom idiotype-reactive T cells were demonstrated. The results indicate that anti-idiotypic antibody may modulate the regulation of in vitro anti-U1-RNP antibody production.

Development of an antigen-specific CD8 suppressor effector clone in man

Takeuchi T., Schlossman S. F., Morimoto C.

Journal of Immunology 141 （ 9 ） 3010 - 3015 1988年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0022-1767

A long-term cultured IL-2-dependent keyhole limpet hemocyanin (KLH)-specific CD8 (T8) suppressor clone (5B9) was generated from a healthy donor hyperimmunized with KLH. The 5B9 clonal population suppressed in vitro anti-KLH antibody response but did not suppress anti-TT antibody response or PWM-driven IgG synthesis. Moreover, 5B9 cells could not suppress anti-TT antibody response even in the presence of free KLH. 5B9 cloned cells suppressed the anti-KLH antibody response of B cells cultured with CD4⁺4B4⁺ cells without requiring the presence of CD8⁺ cells. This KLH-specific CD8 suppressor clone is an effector type rather than an inducer type of suppressor T cell. The cloned cells expressed α- and β-TCR proteins (defined by WT-31 antibody) on their cell surface. More importantly, the CD3:TCR complex was functionally important in the suppression induced by this clone, because after CD3 antigen modulation from its cell surface, the suppressor effector function was abolished.

Defective expression of the 2H4 molecule after autologous mixed lymphocyte reaction activation in systemic lupus erythematosus patients

Takeuchi T., Tanaka S., Steinberg A. D., Matsuyama T., Daley J., Schlossman S. F., Morimoto C.

Journal of Clinical Investigation 82 （ 4 ） 1288 - 1294 1988年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0021-9738

Previous studies demonstrated that patients with active systemic lupus erythematosus (SLE), especially those with active renal disease, had a marked reduction in T4⁺2H4⁺ suppressor inducer cells in their peripheral blood. However, it was puzzling to find that active SLE patients without renal diseases often had normal percentages of T4⁺2H4⁺ cells. In the present study, we attempted to determine whether active SLE patients bearing normal percentages of T4⁺2H4⁺ cells had a defect in their expression of the 2H4 molecule on T4⁺ cells after autologous mixed lymphocyte reaction (AMLR) activation. The peripheral blood lymphocytes (PBL) from 50 SLE patients with normal percentages of T4⁺2H4⁺ cells (≥7% in PBL) were studied and the results were compared with those of 40 normal individuals. The density of the 2H4 molecule on T4 cells from normal controls increased during the 7-d AMLR; in contrast T4 cells from patients with SLE, especially those with active SLE, had defective expression of the 2H4 antigen after AMLR activation. Patients with inactive SLE, like normals, showed an increase in the 2H4 molecule after AMLR activation. Moreover, a strong correlation was observed between percent suppression of pokeweed mitogen (PWM)-driven IgG synthesis and the density of the 2H4 antigen on AMLR-activated T4 cells. Serial analysis of patients with SLE showed that the density of the 2H4 antigen expression and the suppressor inducer activity of AMLR-activated T4 cells were inversely correlated with disease activity. Thus, defective expression of the 2H4 antigen may be an important mechanism for the failure of active SLE patients with normal percentages of T4⁺2H4⁺ cells to generate suppression.

DEFECTS OF AUTOLOGOUS MIXED LYMPHOCYTE REACTION-ACTIVATED IMMUNOREGULATORY T-CELLS IN PATIENTS WITH SYSTEMIC LUPUS-ERYTHEMATOSUS

竹内勤

Scandinavian Journal of Immunology 26 （ 4 ） 363 - 369 1987年10月

研究論文（学術雑誌）, 査読有り, ISSN 0300-9475

THE T4 MOLECULE DIFFERENTIALLY REGULATING THE ACTIVATION OF SUBPOPULATIONS OF T4+ CELLS

竹内勤

Journal of Immunology 139 （ 3 ） 665 - 671 1987年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0022-1767

THE 2H4 MOLECULE BUT NOT THE T3-RECEPTOR COMPLEX IS INVOLVED IN SUPPRESSOR INDUCER SIGNALS IN THE AMLR SYSTEM

竹内勤

Cellular Immunology 107 （ 1 ） 107 - 114 1987年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0008-8749

A DEFECT OF IMMUNOREGULATORY T-CELL SUBSETS IN SYSTEMIC LUPUS-ERYTHEMATOSUS PATIENTS DEMONSTRATED WITH ANTI-2H4 ANTIBODY

竹内勤

Journal of Clinical Investigation 79 （ 3 ） 762 - 768 1987年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0021-9738

INDUCTION OF SUPPRESSION FOLLOWING AUTOLOGOUS MIXED LYMPHOCYTE-REACTION - ROLE OF A NOVEL 2H4 ANTIGEN

竹内勤

European Journal of Immunology 17 （ 1 ） 97 - 103 1987年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0014-2980

The 2H4 molecule but not the T3-receptor complex is involved in suppressor inducer signals in the AMLR system

Takeuchi Tsutomu, Schlossman Stuart F., Morimoto Chikao

Cellular Immunology 107 （ 1 ） 107 - 114 1987年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0008-8749

It is suggested that autologous mixed lymphocyte reaction (AMLR) may play an important role in generating suppressor inducer signals and in down-regulating the immune response following self-major histocompatibility recognition. In the present study, monoclonal antibodies directed at cell surface structures on T4+ cells activated in AMLR were used to define the molecules important in the generation of the suppressor inducer signal. The density of a 200 220-kDa structure, termed 2H4, increased on T4 cells during activation in AMLR and furthermore a strong correlation was observed between the generated suppressor inducer activity of such cells and the density of the 2H4 antigen. More importantly, we showed that treatment of AMLR activated T4 cells with anti-2H4 but not anti-T3 or T4 antibody abolished the suppressor inducer function of these cells. These results suggest that the 2H4 molecule but not the T3-receptor complex plays an important role in generating suppressor inducer signals in the AMLR system. © 1987.

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A defect of immunoregulatory T cell subsets in systemic lupus erythematosus patients demonstrated with anti-2H4 antibody

Morimoto C., Steinberg A. D., Letvin N. L., Hagan M., Takeuchi T., Daley J., Levine H., Schlossman S. F.

Journal of Clinical Investigation 79 （ 3 ） 762 - 768 1987年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0021-9738

The cell surface phenotype of peripheral blood lymphocytes (PBL) of systemic lupus erythematosus (SLE) patients was characterized with the anti-2H4 monoclonal antibody that defines the human suppressor inducer subset. The T4⁺2H4⁺ population of cells has been shown to be critical for the activation of T8⁺ suppressor cells. Patients with SLE had a markedly decreased percentage of T4⁺2H4⁺ cells (13 ± 2%) in their PBL compared with normal controls (21 ± 1%) (P < 0.001). This reduction was greatest in patients with active SLE, especially those with renal disease. Serial analysis of patients with SLE and renal disease showed a correlation between percent positive circulating T4⁺2H4⁺ cells and disease activity. Moreover, there was a significant correlation between a low percentage of T4⁺2H4⁺ cells and decreased suppressor-inducer function in autologous mixed lymphocyte reaction-activated T4⁺ cells from SLE patients. Thus, a deficiency exists in SLE patients with active renal disease in the T4⁺2H4⁺ suppressor-inducer T cell subset.

Defects of autologous mixed lymphocyte reaction-activated immunoregulatory T cells in patients with systemic lupus erythematosus

Koide J., Takeuchi T., Hosono O., Takano M., Abe T.

Scandinavian Journal of Immunology 26 （ 4 ） 363 - 369 1987年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0300-9475

The present study was undertaken to determine the nature of the immunoregulatory T-cell defect after autologous mixed lymphocyte reaction (AMLR) activation in patients with systemic lupus erythematosus (SLE). Although AMLR was decreased in patients with SLE compared with normals, there was no difference in major proliferative cells (T4 cells and T4⁺JRA⁺ subset) in response to AMLR. Functional activity of AMLR-stimulated T4 subsets in patients with SLE and normals was examined in helper and suppressor/inducer assay, using pokeweed mitogen (PWM)-derived IgG synthesis. The T4⁺JRA^- (helper) subset from SLE patients showed no greater activity than normals. However, the T4⁺JRA^- (helper) subset from SLE patients showed no greater activity than normals. However the T4⁺JRA⁺ (suppressor/inducer) subset from SLE patients showed decreased suppression induction compared with normals. This defect in the suppressor/inducer function was demonstrated even in patients with inactive SLR or in remission.

The T4 molecule differentially regulating the activation of subpopulations of T4⁺ cells

Takeuchi T., Schlossman S. F., Morimoto C.

Journal of Immunology 139 （ 3 ） 665 - 671 1987年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0022-1767

It has been demonstrated that the T4⁺2H4⁺ subset functioned as a suppressor inducer cell, whereas the reciprocal T4⁺2H4^- subset provided help for B cell Ig production. In the present studies, a series of monoclonal antibodies to cell surface structures expressed on subsets of cells were examined for their effects on the proliferative and immunoregulatory functions generated in AMLR. We demonstrated that anti-T4 antibody preferentialy inhibited the proliferative response of the T4⁺2H4⁺ but not T4⁺2H4^- cells against self-MHC antigens. In contrast, anti-T3 and anti-Ia antibodies inhibited the response of both subsets of cells. This subset preference of anti-T4 antibody was not attributable to either the isolation procedures used or a shift in the kinetics of proliferation to autologous self-MHC antigens. Moreover, both IL 2 production and the immunoregulatory function of the T4⁺2H4⁺ subset was profoundly inhibited by anti-T4 antibody, whereas the T4⁺2H4^- subset was minimally influenced. In the absence of Ia molecules, T4⁺2H4⁺ but not T4⁺2H4^- cell proliferation was inhibited with anti-T4 antibody. Together, these results suggest that the T4 molecule plays a distinct functional role in the differential triggering of subsets of T4⁺ cells.

Induction of suppression following autologous mixed lymphocyte reaction; role of a novel 2H4 antigen

Takeuchi T., Rudd C. E., Schlossman S. F., Morimoto C.

European Journal of Immunology 17 （ 1 ） 97 - 103 1987年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0014-2980

In this study, we have investigated the cellular and molecular basis for immunoregulatory function of T4⁺ cells after autologous mixed lymphocyte reaction (AMLR) activation. We demonstrated that the T4⁺2H4⁺ subset but not the T4⁺2H4^- subset can proliferate maximally in response to autologous non-T cells. T4⁺ cells activated by AMLR exerted suppressor activity on pokeweed mitogen-driven IgG synthesis of autologous peripheral blood lymphocytes. The suppressor activity by AMLR-activated T4⁺ cells required the presence of fresh T8⁺ cells in the secondary culture, indicating that AMLR-activated T4⁺ cells functioned as a suppressor inducer rather than as a suppressor effector population. Following activation of T4⁺ cells in AMLR, it is the T4⁺2H4⁺ subset which induces suppression through the T8 population. Moreover, the treatment of AMLR-activated T4⁺2H4⁺ cells with anti-2H4 antibody, but not other antibodies, resulted in the abolishment of suppressor inducer function of such cells, suggesting that the 2H4 molecule itself may be involved in the suppressor induced function. The 2H4 antigen on such cells was shown to be comprised of 220-kDa and 200-kDa glycoproteins. These results support the notion that the AMLR may play an important role in generating suppressor inducer signals and in down-regulating the immune response following self major histocompatibility complex recognition. More importantly, the present studies indicate that the 2H4 antigen on T4 cells serves not only as a phenotypic marker of suppressor inducer cells, but may have a functionally important role itself in inducing suppression.

Direct demonstration of immunoregulatory T-cell defects in patients with systemic lupus erythematosus

Koide J., Takano M., Takeuchi T., Hosono O., Amano K., Homma M., Abe T.

Scandinavian Journal of Immunology 23 （ 4 ） 449 - 459 1986年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0300-9475

The present study was undertaken to determine directly whether immunoregulatory T cells have a defective suppressor function in patients with systemic lupus erythematosus (SLE), and whether anti-T-cell antibodies are essential for immunoregulatory T-cell defects. Peripheral blood T cells and T-cell subsets were determined in 52 SLE patients. The ratio of T4 to T8 cells was distributed over a wider range in patients with SLE than in the controls. Patients with SLE were divided into three groups (low, normal and high) by the T4/T8 ratio. Lymphocytes from 12 SLE patients (7 with low and 5 with high T4/T8 ratios) were studied extensively. Their disease was inactive or in remission. Anti-T-cell antibodies were not detected, and yet the patients had immunological abnormalities characterized by the presence of antinuclear antibodies and hypergammaglobulinaemia. The SLE patients with high T4/T8 ratios had a decreased number of T8 cells, and defective suppressor-effector cells. In contrast, patients with low T4/T8 ratios had decreased T4 cells and/or increased T8 cells, and defective suppressor-inducer cells. Two patients with low T4/T8 ratios had both suppressor-effector and suppressor-inducer cell defects. These results indicate that immunoregulatory circuits in SLE patients are heterogeneous and that immunoregulatory defects exist even when the disease is inactive or in remission. Anti-T-cell antibodies were not essential for such immunoregulatory defects. Thus, immunoregulatory T-cell defects and the development of SLE may be independent conditions due to other unknown causes.

DNA-daunorubicin complexes specifically suppress in vitro spontaneous anti-DNA antibody production in lymphocytes of patients with systemic lupus erythematosus

Takeuchi T., Koide J., Hosono O., Amano K., Homma M., Masuho Y., Morimoto C., Takano M., Abe T.

Arthritis and Rheumatism 29 （ 10 ） 1216 - 1222 1986年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0004-3591

Elevated production of anti-DNA antibody in patients with systemic lupus erythematosus (SLE) is a central problem in the pathogenesis of tissue injury. In the present study, we attempted to manipulate anti-DNA antibody production through the antigen-cytotoxic drug conjugates, DNA-daunorubicin complexes. The effect of DNA-daunorubicin complexes was determined by examining SLE lymphocytes for spontaneous in vitro production of anti-DNA antibody. These complexes, at 2 μg/ml, suppressed anti-DNA antibody production, but not total IgG production, which suggests that specific suppression of anti-DNA antibody production was achieved at this concentration. We believe that the DNA-daunorubicin complexes affected mainly B cells, since such suppression was obtained by treating B cells, as well as B plus T cells. Furthermore, the complexes had no effect on the proliferative responses of SLE T cells to DNA, phytohemagglutinin, or concanavalin A. These results indicate that DNA-daunorubicin complexes may have the potential for selectively suppressing anti-DNA antibody production in patients with SLE.

The role of the 2H4 molecule in the generation of suppressor function in Con A-activated T cells

Morimoto C., Letvin N. L., Rudd C. E., Hagan M., Takeuchi T., Schlossman S. F.

Journal of Immunology 137 （ 10 ） 3247 - 3253 1986年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0022-1767

The molecular basis for the suppression generated in a concanavalin A (Con A)-activated T cell culture remains unknown. In this study, we have attempted to determine whether the 2H4 and 4B4 molecules on Con A-activated T cells play some role in the generation of suppression by such cells. We have shown that Con A-activated suppressor cells belong to the 2H4⁺ subset of T cells but not the 4B4⁺ (2H4^-) subset. Con A-activated T cell exerted their optimal suppressor function on day 2 in culture, a time at which the expression of 2H4 on such cells was maximal and 4B4 was minimal. Furthermore, the stimulation of T cells with the higher concentration of Con A generated the stronger suppressor function. At the same time, both 2H4 expression and density were increased and 4B4 expression and density were decreased on such Con A-activated T cells. More importantly, the treatment of Con A-activated T cells with anti-2H4 antibody but not with anti-4B4, anti-TQ1, or anti-T4 antibodies can block the suppressor function of such cells. Taken together, the above results strongly suggest that the 2H4 molecule itself may be involved in the generation of suppressor function in Con A-activated T cells. The 2H4 antigen on such cells was shown to be comprised of 220,000 and 200,000 m.w. glycoproteins. Thus this study indicates that the 220,000 and 200,000 m.w. structure of the 2H4 molecule may itself play a crucial role in the generation of suppressor signals of Con A-activated cells.

Spontaneous production of antibodies to deoxyribonucleic acids in patients with systemic lupus erythematosus

Takeuchi Tsutomu

Clinical Immunology and Immunopathology 35 （ 1 ） 47 - 56 1985年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0090-1229

In vitro spontaneous anti-DNA antibody production in patients with systemic lupus erythematosus (SLE) was examined. SLE lymphocytes produced IgG and IgM anti-DNA antibody from the third culture day, and reached a plateau on the seventh culture day. This anti-DNA antibody activity in 7-day culture suppernatant was abolished by pretreatment of the lymphocytes with cycloheximide, suggesting de novo immunoglobulin synthesis was required for this spontaneous anti-DNA antibody production. Lymphocytes from patients with rheumatoid arthritis (RA) and other collagen diseases including progressive systemic sclerosis, polymyositis/dermatomyositis, and polyarteritis nodosa did not produce IgG and IgM anti-DNA antibody spontaneously, but SLE lymphocytes produced substantial amounts of IgG and IgM anti-DNA antibody spontaneously. Furthermore, active SLE produced a larger amount of IgG anti-DNA antibody than inactive SLE. We observed a significant negative correlation between the number of Ia⁺ T cells and IgG, but not IgM, anti-DNA antibody production. Furthermore, spontaneous IgG anti-DNA antibody production was elevated after pretreatment of SLE T cells with anti-Ia and complement, suggesting that Ia⁺ T cells in SLE bring about suppression of autologous B cells producing IgG anti-DNA antibody. © 1985.

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Suppression of rheumatoid factor synthesis by antiidiotypic antibody in rheumatoid arthritis patients with cross-reactive idiotypes

Takeuchi T., Hosono O., Koide J., Homma M., Abe T.

Arthritis and Rheumatism 28 （ 8 ） 873 - 881 1985年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0004-3591

The effect of antiidiotypic antibody on the in vitro production of rheumatoid factor was studied in rheumatoid arthritis patients with cross-reactive idiotypic determinants. Antiidiotypic antibodies (ascites IgG) were developed against monoclonal rheumatoid factor (Ka m-RF) by a cell fusion procedure. These antibodies were idiotype-specific, since: 1) they reacted only with F(ab')₂ fragment of Ka m-RF; 2) they failed to react with normal IgM without rheumatoid factor activity; and 3) their F(ab')₂ fragment inhibited the rheumatoid factor activity of Ka m-RF. The antiidiotypic antibody strongly suppressed the in vitro production of rheumatoid factor by lymphocytes from unrelated rheumatoid arthritis patients with cross-reactive idiotypes. The suppression was specific, since ascites IgG failed to suppress in vitro anti-keyhole limpet hemocyanin antibody production by the lymphocytes. These results indicate that antiidiotypic antibody may influence the regulation of rheumatoid factor production in patients with rheumatoid arthritis.

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Cellular mechanism of DNA-specific antibody synthesis by lymphocytes from systemic lupus erythematosus patients

Takeuchi T., Abe T., Koide J., Hosono O., Morimoto C., Homma M.

Arthritis and Rheumatism 27 （ 7 ） 766 - 773 1984年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0004-3591

The cellular mechanism of anti-DNA antibody synthesis in patients with systemic lupus erythematosus (SLE) was studied by DNA-specific solid-phase radioimmunoassay. Anti-DNA antibody synthesis in response to DNA was T-dependent, and the experiments with reconstituted lymphocytes from identical twins discordant for SLE showed that B cells and T cells from SLE patients must cooperate to synthesize anti-DNA antibody. Anti-DNA antibody synthesis by lymphocytes from patients with inactive SLE was enhanced by T4 cells and suppressed by T8 cells in response to DNA. Although T4 cells from patients with active SLE could enhance anti-DNA antibody synthesis by autologous B cells, their T8 cells could not suppress anti-DNA antibody synthesis by autologous B cells. These results indicate that elevated anti-DNA antibody synthesis in response to DNA in patients with active SLE is due to abnormalities of both SLE B cells and SLE T cells. They further indicate that dysfunction of T8 cells from patients with active SLE may, in part, be responsible for deficient regulation of anti-DNA antibody synthesis.

Anti-idiotypic antibodies in a patient with monoclonal rheumatoid factor after pneumococcal bacteremia

Abe T., Takeuchi T., Kiyotaki M., Koide J., Hosono O., Homma M., Otake T., Kano S.

Journal of Immunology 132 （ 5 ） 2381 - 2385 1984年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0022-1767

A 51-yr-old Japanese female patient with monoclonal IgM gammopathy with rheumatoid factor activity was admitted because of pneumococcal bacteremia. About 2 wk after admission, her rheumatoid factor activity became undetectable by RAHA test and radioimmunoassay, subsequent to the initial marked elevation. The suppressive capacity of the patient's IgG fraction on the rheumatoid activity of her monoclonal IgM on January 11 was determined. The IgG fraction obtained on February 22 blocked the binding of the rheumatoid factor to rabbit IgG. The suppressive activity in the IgG fraction of February 22 was shown to be localized within the F(ab')₂ fragment. Furthermore, the specificity of the suppressive serum factor was shown by the inability to block the binding of SRBC coupled with diazotized phosphorylcholine to anti-pneumococcal antibody. Thus, the marked reduction of rheumatoid factor activity was considered to result from anti-idiotypic antibody transiently appearing in her serum after pneumococcal bacteremia.

Suppressor T cell function in patients with rheumatoid arthritis complicated by vasculitis

Abe T., Takeuchi T., Koide J., Hosono O., Homma M., Morimoto C., Yokohari R.

Arthritis and Rheumatism 27 （ 7 ） 752 - 759 1984年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0004-3591

Concanavalin A (Con A)-induced suppressor T cell activity was determined in 10 rheumatoid arthritis (RA) patients with vasculitis, 34 RA patients without vasculitis, and 10 healthy individuals. The percent Con A-induced suppression in RA patients with vasculitis was 24.6. In contrast, it was 68.4% in those RA patients without vascular lesions. Further, the proportion of T cells reactive with OKT8 monoclonal antibody was also decreased in RA patients with vasculitis. Accordingly, the reduced Con A-induced suppressor T cell activity in these RA patients resulted, in part, from the reduction in the number of cells of the suppressor T cell subset. Those patients with vascular lesions also had a higher percentage of positive antilymphocytotoxic antibodies than RA patients without vasculitis. Since the differences in Con A-induced suppressor T cell activity and frequency of positive antilymphocytotoxic antibodies were so great, we believe RA patients with vasculitis could be recognized as a disease group distinct from RA patients without vasculitis.

Functional differences of anti-T-cell antibody in patients with systemic lupus erythematosus and ulcerative colitis

Abe T., Morimoto C., Toguchi T., Kiyotaki M., Takeuchi T., Koide J., Asakura H., Tsuchiya M., Homma M.

Scandinavian Journal of Immunology 18 （ 6 ） 521 - 530 1983年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0300-9475

The loss of suppressor T-cell function results in an abundant production of autoantibodies in systemic lupus erythematosus (SLE). As a cause of this suppressor T-cell defect, anti-T-cell antibody seems to be of prime importance. On the other hand, anti-T-cell antibodies can be detected in various other autoimmune diseases, but their functional characteristics have not been determined. In the present study, the functional characteristics of anti-T-cell antibody from a selected subgroup of patients with ulcerative colitis (UC) were compared with those from patients with SLE. Anti-T-cell antibody from the patients with SLE reacted with a T8 subset, resulting in a suppressor defect, whereas anti-T-cell antibody from the UC patients reacted primarily with a T4 subset. Functionally, SLE^- T cells failed to proliferate in response to concanavalin A, whereas UC^- T cells from UC patients failed to proliferate in response to phytohaemagglutinin. In the Ig synthesis system, both SLE^- and UC^- T cells increased Ig production of B cells. Since UC⁺ T cells did not contribute to the generation of Con-A-inducible suppressor activity, we believe that serum from the selected subgroup of patients with UC reacted with the inducer T-cell subset.

In vitro immune response of SLE lymphocytes. The mechanism involved in B-cell activation

Takeuchi T., Abe T., Kiyotaki M., Toguchi T., Koide J., Morimoto C., Homma M.

Scandinavian Journal of Immunology 16 （ 5 ） 369 - 377 1982年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0300-9475

Peripheral blood lymphocytes from 26 patients with systemic lupus erythematosus (SLE) and six normal individuals were tested for IgG synthesis in the presence or absence of PWM. Lymphocytes from patients with active SLE synthesized increased amounts of IgG in the absence of PWM and reduced amounts of IgG in the presence of PWM. Serum from patients with active SLE had an enhancing effect on the in vitro IgG synthesis of normal lymphocytes. The IgG or F(ab')₂ fractions of SLE serum retained the enhancing effect on in vitro IgG synthesis, and the enhancing activity was absorbed by human spleen cells. As little as 4 h of incubation with SLE serum was needed for the enhancing activity of normal lymphocytes. Treatment of B lymphocytes appeared to be of main importance for an increase in the in vitro IgG synthesis of SLE serum-treated lymphocytes. These results suggest that anti-B-lymphocyte antibodies from patients with active SLE are responsible in part for the hyperactive response of SLE B lymphocytes.

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Mitogenic responses to lipopolysaccharide by B lymphocytes from patients with systemic lupus erythematosus

Abe T., Toguchi T., Takeuchi T., Kiyotaki M., Homma M.

Scandinavian Journal of Immunology 15 （ 5 ） 475 - 482 1982年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0300-9475

Peripheral blood lymphocytes from 43 patients with systemic lupus erythematosus (SLE) and from age- and sex-matched normal controls were cultured with lipopolysaccharide (LPS) to examine the response to the polyclonal B-cell activator. Lymphocytes from active SLE patients incorporated 4840±471 (mean ±SE) cpm in response to LPS, whereas lymphocytes from inactive SLE patients incorporated 6906±897 cpm. In contrast, lymphocytes from normal individuals incorporated 7452±1126 cpm. Ig synthesis of lymphocytes from active SLE in response to LPS stimulation was also less than that of normal individuals. The helper T-cell function of active SLE, as examined by co-culturing irradiated SLE lymphocytes with unirradiated normal lymphocytes, was normal. These results thus suggested that a defect of B lymphocytes exists in active SLE patients. This B-cell defect and T suppressor cells apparently play an important role in the pathogenesis of SLE.

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In vitro anti-DNA antibody synthesis by peripheral blood lymphocytes in patients with systemic lupus erythematosus

Kiyotaki Masaya, Toguchi Takashi, Abe Tohru, Takeuchi Tsutomu, Morimoto Chikao, Homma Mitsuo

Clinical Immunology and Immunopathology 21 （ 2 ） 237 - 246 1981年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0090-1229

In vitro anti-DNA antibody synthesis by peripheral blood lymphocytes from systemic lupus erythematosus (SLE) patients after native DNA (nDNA) stimulation was studied by the Farr assay after digestion with deoxyribonuclease I. Active SLE lymphocytes synthetized IgG and anti-DNA antibody with nDNA stimulation but inactive SLE and normal lymphocytes did not. Binding of ¹⁴C-labeled Ig and [³H]DNA showed that DNA-binding Ig was actively secreted by SLE lymphocytes. SLE antilymphocyte antibody (ALA)-sensitive T cells (SLE⁺ T cells) and unreactive T cells (SLE^- T cells) were separated by anti-human Ig antibody-coated dishes to determine their effect on antibody synthesis. Inactive SLE B cells synthetized both IgG and anti-DNA antibody after nDNA stimulation with autologous SLE^- T cells but stimulation with SLE⁺ T cells did not result in synthesis of either. Normal B cells did not synthetize IgG even with autologous SLE^- T cells. These results indicate that active and inactive SLE patients have autoreactive lymphocytes against nDNA which synthetize anti-DNA antibody and are regulated by ALA-sensitive T cells (possibly deficient in active SLE). © 1981.

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INVITRO ANTI-DNA ANTIBODY-SYNTHESIS BY PERIPHERAL-BLOOD LYMPHOCYTES IN PATIENTS WITH SYSTEMIC LUPUS-ERYTHEMATOSUS

竹内勤

Clinical Immunology and Immunopathology 21 （ 2 ） 237 - 246 1981年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0090-1229

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