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Papers - Kikuchi, Jun

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Reversible cerebral vasoconstriction syndrome triggered by tacrolimus mimicked neuropsychiatric involvement in systemic lupus erythematosus

Jun Inamo, Jun Kikuchi, Katsuya Suzuki, Yuko Kaneko, Hidekata Yasuoka, Hirokazu Fujiwara, Kunihiro Yamaoka, Tsutomu Takeuchi

Modern Rheumatology Case Reports (Informa UK Limited) 3 ( 2 ) 119 - 123 2019.07

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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 2018.09

Accepted, ISSN 2326-5191

Initial predictors of poor survival in myositisassociated interstitial lung disease: A multicentre cohort of 497 patients

Sato S., Masui K., Nishina N., Kawaguchi Y., Kawakami A., Tamura M., Ikeda K., Nunokawa T., Tanino Y., Asakawa K., Kaneko Y., Gono T., Ukichi T., Kaieda S., Naniwa T., Kuwana M., Okano Y., Yamaguchi Y., Taniguchi Y., Kikuchi J., Kubo M., Watanabe M., Harada T., Kazuyori T., Kameda H., Kaburaki M., Matsuzawa Y., Yoshida S., Yoshioka Y., Hirai T., Wada Y., Ishii K., Fujiwara S., Saraya T., Morimoto K., Hara T., Suzuki H., Shibuya H., Muro Y., Aki R., Shibayama T., Ohshima S., Yasuda Y., Terada M., Kawahara Y.

Rheumatology (United Kingdom) (Rheumatology (United Kingdom)) 57 ( 7 ) 1212 - 1221 2018.07

ISSN 14620324

© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. Objective. To identify initial predictors of poor survival in patients with PM/DM-associated interstitial lung disease (ILD). Methods. We established a multicentre retrospective cohort of incident cases of PM/DM-associated ILD from 44 institutions across Japan (Multicentre Retrospective Cohort of Japanese Patients with Myositisassociated ILD, JAMI). Inclusion criteria were an onset age ≥16 years; PM/DM or clinically amyopathic DM according to the published criteria; imaging evidence of ILD; and availability of serum samples for assays of autoantibodies such as anti-melanoma differentiation-associated gene 5 and anti-aminoacyl tRNA synthetase. We collected demographic data and clinical characteristics recorded at the time of diagnosis, as well as follow-up survival data. Predictors of ILD-related mortality were identified by univariate and multivariate analyses. Results. JAMI enrolled a cohort of 497 patients with PM (15%), classic DM (32%) and clinically amyopathic DM (53%). During the observation period (median 20 months), 76 died of respiratory insufficiency directly related to ILD. Univariate analysis revealed several initial parameters associated with ILD mortality, including demographic, clinical, laboratory, imaging and autoantibody variables. We used multivariate analysis with a stepwise selection of parameters to generate an appropriate predictive model, and identified the following independent risk factors for ILD mortality: age at onset ≥60 years [hazard ratio (HR) = 4.3, 95% CI: 2.4, 7.5], CRP ≥1 mg/dl (HR = 2.6, 95% CI: 1.5, 4.8), peripheral capillary oxygen saturation <95% (HR = 2.0, 95% CI: 1.2, 3.4) and anti-melanoma differentiation-associated gene 5 antibody (HR = 7.5, 95% CI: 2.8, 20.2). Conclusion. We established a large cohort of incident cases of PM/DM-associated ILD, and successfully identified independent predictors of short-term ILD mortality.

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Efficacy and tolerability of six-week extended dosing interval with tocilizumab therapy in a prospective cohort as remission maintenance in patients with rheumatoid arthritis

Jun Kikuchi, Tsuneo Kondo, Akiko Shibata, Ryota Sakai, Yusuke Okada, Kentaro Chino, Ayumi Okuyama, Takahiko Kurasawa, Hirofumi Takei, Koichi Amano

Modern Rheumatology (Taylor and Francis Ltd) 28 ( 3 ) 444 - 451 2018.05

Accepted, ISSN 14397595

Objectives: To prospectively evaluate the efficacy and tolerability of a six-week extended dosing interval with tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) in sustained remission. Methods: Patients who received over six doses of intravenous TCZ in clinical remission (disease activity score [DAS] 28–erythrocyte sedimentation rate [ESR] ≤ 2.6) maintained over 3 months between December 2013 and December 2015 were included. Flare was defined as DAS28-ESR &gt
3.2 at two consecutive visits. Results: Twenty-five patients were enrolled
87.5% achieved clinical remission at week 54 after six-week extension and 95.5% achieved a van der Heijde modified total Sharp score (ΔmTSS) ≤0.5. The Health Assessment Questionnaire Disability Index (HAQ-DI) did not increase during 54 weeks. HAQ-DI at baseline and ΔDAS28-ESR at week six positively correlated with increase in DAS28-ESR at week 54. ΔSwollen joint count at week six positively correlated with ΔmTSS at week 54. A total of 12 adverse events occurring in 10 patients did not lead to cessation of TCZ except for one case of recurrent lymphoproliferative disorder at week five. Conclusion: A six-week extended dosing interval of TCZ for patients with RA in sustained remission is proposed as an acceptable treatment option for maintaining efficacy and tolerability.

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Persistent fever and destructive arthritis caused by dialysis-related amyloidosis

Kotaro Matsumoto, Jun Kikuchi, Yuko Kaneko, Hidekata Yasuoka, Kazuko Suzuki, Hirobumi Tokuyama, Kaori Kameyama, Kunihiro Yamaoka, Tsutomu Takeuchi

Medicine (United States) (Lippincott Williams and Wilkins) 97 ( 1 ) e9359 2018.01

Accepted, ISSN 00257974

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 &gt
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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[Mixed connective tissue disease with pulmonary hypertension developing in a chronic myeloid leukemia patient on dasatinib treatment].

Watanuki S, Kikuchi T, Toyama T, Abe R, Nakayama H, Karigane D, Shimizu T, Kikuchi J, Matsumoto K, Yasuoka H, Kataoka M, Okamoto S, Mori T

[Rinsho ketsueki] The Japanese journal of clinical hematology 59 ( 2 ) 174 - 177 2018

Accepted, ISSN 0485-1439

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

Ryusuke Anan, Mitsuhiro Akiyama, Yuko Kaneko, Jun Kikuchi, Kazuko Suzuki, Shiro Matsubara, Tsutomu Takeuchi

Medicine (United States) (Lippincott Williams and Wilkins) 96 ( 48 ) e8710 2017.12

Accepted, ISSN 1536-5964

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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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

Hayato Yamazaki, Fumio Hirano, Tsutomu Takeuchi, Koichi Amano, Jun Kikuchi, Mari Kihara, Waka Yokoyama, Takahiko Sugihara, Kenji Nagasaka, Hiroyuki Hagiyama, Yoshinori Nonomura, Ryoko Sakai, Michi Tanaka, Ryuji Koike, Toshihiro Nanki, Hitoshi Kohsaka, Nobuyuki Miyasaka, Masayoshi Harigai

MODERN RHEUMATOLOGY (TAYLOR & FRANCIS LTD) 27 ( 5 ) 787 - 794 2017

Accepted, ISSN 1439-7595

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 (DmTSS <= 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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Corticosteroid-free treatment of tocilizumab monotherapy for microscopic polyangiitis: a single-arm, single-center, clinical trial

Ryota Sakai, Tsuneo Kondo, Jun Kikuchi, Akiko Shibata, Kentaro Chino, Ayumi Okuyama, Hirofumi Takei, Koichi Amano

Modern Rheumatology 26 ( 6 ) 900 - 907 2016.11

ISSN 1439-7595

Objectives: To assess the efficacy of tocilizumab (TCZ) monotherapy for the remission induction of microscopic polyangiitis (MPA) in a prospective single-arm, single-center, cohort, pilot study. Methods: Eligible patients were aged between 20 and 80 years and were newly diagnosed with MPA according to Watts’ classification algorithm. Seven patients received 8 mg/kg of intravenous TCZ fortnightly for the first 2 months (5 courses), and monthly for the next 10 months (10 courses). One year after TCZ monotherapy, the patients were followed-up without any treatment. The protocol did not permit the use corticosteroids or any other immunosuppressants. Complete remission (CR) was defined as the Birmingham Vasculitis Activity Score of 0 at two consecutive visits made at least a month apart. Results: CR was achieved in two of six patients (33.3%) at 6 months and three patients (50.0%) at 12 months. Two patients were withdrawn: one because of inefficacy at 6 weeks and the other because of flare at 6 months. One patient voluntarily withdrew after CR at 3 months. Four patients (66.7%) could be kept drug-free after 1 year of TCZ without relapse for 6–15 months at the last visit. Conclusion: TCZ monotherapy may be an alternative treatment strategy in some patients with MPA.

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Proportions of Circulating Follicular Helper T Cells and Complement Levels, White Blood Cell Counts, and Skin Manifestations in Patients with Active Systemic Lupus Erythematosus

Jun Kikuchi, Masaru Takeshita, Katsuya Suzuki, Yoshiaki Kassai, Takahiro Miyazaki, Tsutomu Takeuchi

ARTHRITIS & RHEUMATOLOGY (WILEY) 68 2016.10

Accepted, ISSN 2326-5191

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. and Takeuchi, T.

Intern Med (JAPAN SOC INTERNAL MEDICINE) 55 ( 12 ) 1661 - 5 2016

Accepted, ISSN 1349-7235

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

Masaru Takeshita, Katsuya Suzuki, Jun Kikuchi, Keisuke Izumi, Takahiko Kurasawa, Keiko Yoshimoto, Koichi Amano, Tsutomu Takeuchi

CYTOKINE (ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD) 75 ( 2 ) 222 - 227 2015.10

Accepted, ISSN 1043-4666

Objective: Pro-inflammatory cytokines, especially TNF alpha, 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 TNFO. 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-1 beta, IL-2, IL-6, IL-6R, IL-8, IL-10, IL-12, TNF alpha, TNF beta, IFN gamma, 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. IFN gamma was gradually increased only in the non-remission subgroup of the IFX group, and not at all in the ETN group. TNF(3 increased after starting IFX regardless of clinical efficacy.
Conclusion: IL-6 inhibition is a pathway affected by both IFX and ETN. In addition, IFN gamma increase is a distinctive feature of the inefficacy of IFX. (C) 2015 Elsevier Ltd. All rights reserved.

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Peripheral blood CD4(+)CD25(+)CD127(low) 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. and Takeuchi, T.

Arthritis Res Ther (BIOMED CENTRAL LTD) 17 10 - 10 2015

Accepted, ISSN 1478-6362

INTRODUCTION: 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(+)CD127(low) 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 52 weeks. 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 (rho = -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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Baseline levels of soluble interleukin-6 receptor predict clinical remission in patients with rheumatoid arthritis treated with tocilizumab: implications for molecular targeted therapy

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

ANNALS OF THE RHEUMATIC DISEASES (BMJ PUBLISHING GROUP) 73 ( 5 ) 945 - U167 2014.05

Accepted, ISSN 0003-4967

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[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 101 ( 10 ) 2926 - 2942 2012.10

Accepted, ISSN 0021-5384

A Case of IgA-related Enteropathy Complicated with Gastrointestinal Bleeding and Progressive IgA Nephropathy: A Possible Variant Henoch-Schonlein Purpura?

Shoko Nakamura, Tadakazu Hisamatsu, Jun Kikuchi, Masayuki Adachi, Yoshiyuki Yamagishi, Hiroyuki Imaeda, Naoki Hosoe, Makoto Naganuma, Hirotoshi Ebinuma, Susumu Okamoto, Takanori Kanai, Haruhiko Ogata, Hironari Hanaoka, Yoshiaki Furuya, Yoshinaga Kawano, Kanako Bokuda, Hiroyuki Sasamura, Hiroshi Uchida, Takashi Endo, Akinori Hashiguchi, Kaori Kameyama, Makio Mukai, Toshifumi Hibi

INTERNAL MEDICINE (JAPAN SOC INTERNAL MEDICINE) 49 ( 16 ) 1755 - 1761 2010

Accepted, ISSN 0918-2918

Here, we report an adult patient with IgA-related enteropathy complicated with massive intestinal bleeding and acute renal failure, but without skin lesions. Surgical resection of the small intestine and steroid pulse therapy was performed. Histopathology revealed significant deposition of IgA and C3 in the small vessels of the intestine and the kidney mesangium. Although skin purpura was absent, the histopathology and clinical manifestations suggested that the pathophysiology was similar to Henoch-Schnlein purpura (HSP), implying IgA-related enteropathy as a subclass of HSP. Retrospective analysis indicates that terminal ileum lesions may be a poor prognostic indicator.

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