Faculty Profiles - KATSUYAMA Takayuki

Papers - KATSUYAMA Takayuki

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Implications of serum calcitonin gene-related peptide and type I interferon in systemic lupus erythematosus-associated headaches

Shu Sugimoto, Yasuhiro Shimojima, Dai Kishida, Takanori Ichikawa, Ryota Takamatsu, Nobuyuki Yajima, Kunihiro Ichinose, Toshimasa Shimizu, Ryusuke Yoshimi, Takashi Kida, Takayuki Katsuyama, Yusuke Matsuo, Hiroshi Kajiyama, Ayuko Takatani, Yoshiki Sekijima

Lupus 2025.4

Publishing type：Research paper (scientific journal) Publisher：SAGE Publications

Objective

Headache is a common neurological symptom in patients with systemic lupus erythematosus (SLE). Calcitonin gene-related peptide (CGRP) is a potential chemical mediator of headaches, while type I interferon (IFN) plays a pivotal role in the immune system of SLE. This study investigated the implications of CGRP and type I IFNs as headache biomarkers in patients with SLE.

Methods

We used clinical information and serum samples from 144 patients with SLE from a Japanese multicenter cohort and a biobank. Serum CGRP, IFN-α, and IFN-β levels, which were measured using enzyme-linked immunoassay, were compared among patients with headache, those without headache, and 20 healthy controls (HC). These levels were compared based on the severity of daily disability caused by headaches as determined using the Migraine Disability Assessment.

Results

Of the 144 patients, 60 had headache (median age, 42 years; 56 women) and were significantly younger than patients without headache (median age, 49 years; 77 women) ( p < .005). Both groups had a median SLE Disease Activity Index 2000 score of 4.0, which was not significantly different, whereas photosensitivity was significantly more prevalent in patients with headache than in those without headache ( p < .05). Serum CGRP and IFN-α levels were not significantly different between patients with headache, those without headache, and HC. Serum IFN-β levels were significantly higher in patients with headache than in those without headache ( p < .005), while being significantly lower in both patients with and without headache than in HC ( p < .005). No significant differences in serum CGRP, IFN-α and IFN-β levels were observed based on the severity of daily disability related to headaches.

Conclusion

Serum CGRP and type I IFNs levels may not be involved in SLE-associated headaches.

DOI： 10.1177/09612033251332789

Other Link： https://journals.sagepub.com/doi/full-xml/10.1177/09612033251332789

Dyspnea with Hemidiaphragm Elevation in a Patient with Giant Cell Arteritis: A Case Report

Yosuke Asano, Yoshinori Matsumoto, Natsuki Kubota, Yuya Terajima, Kazuya Matsumoto, Kenta Shidahara, Kei Hirose, Takato Nakadoi, Shoichi Nawachi, Yu Katayama, Yoshia Miyawaki, Eri Katsuyama, Takayuki Katsuyama, Mariko Takano-Narazaki, Ken-Ei Sada, Jun Wada

Internal Medicine 2025

Pericardial artery lymphoma in a patient with dermatomyositis: A case report. International journal

Kei Hirose, Takayuki Katsuyama, Natsuki Kubota, Yuya Terajima, Kazuya Matsumoto, Kenta Shidahara, Takato Nakadoi, Shoichi Nawachi, Yu Katayama, Yoshia Miyawaki, Eri Katsuyama, Mariko Narazaki-Takano, Yoshinori Matsumoto, Noboru Asada, Ken-Ei Sada, Jun Wada

Modern rheumatology case reports 2024.11

Language：English Publishing type：Research paper (scientific journal)

A woman in her 60s presented with erythema on both elbows, dyspnea on exertion, discomfort, and swelling of the left upper extremity, followed by swelling and myalgia of the right upper and lower extremities. She was diagnosed with anti-TIF1γ antibody-positive dermatomyositis with interstitial pneumonia. The initial screening tests for malignant diseases including contrast-enhanced CT, upper and lower endoscopy, and gynecological examination did not reveal any obvious abnormalities. The patient experienced two recurrent episodes of muscle weakness and dysphagia during treatment with intravenous glucocorticoids and cyclophosphamide. Five months after diagnosis, a bone marrow biopsy and positron emission tomography- computed tomography (PET-CT) scan revealed a coronary malignant lymphoma with suspected systemic metastasis. Although chemotherapy was initiated, the patient ultimately succumbed to alveolar hemorrhage. Coronary lymphoma is very rare and there has been no report of a cases associated with myositis. PET-CT may be useful for searching malignancy in anti-TIF1γ antibody-positive dermatomyositis cases of recurrent relapse.

DOI： 10.1093/mrcr/rxae065

Association between discontinuity of care and patient trust in the usual rheumatologist among patients with systemic lupus erythematosus: a cross-sectional study

Yu Katayama, Yoshia Miyawaki, Kenta Shidahara, Shoichi Nawachi, Yosuke Asano, Eri Katsuyama, Takayuki Katsuyama, Mariko Takano-Narazaki, Yoshinori Matsumoto, Nao Oguro, Nobuyuki Yajima, Yuichi Ishikawa, Natsuki Sakurai, Chiharu Hidekawa, Ryusuke Yoshimi, Shigeru Ohno, Takanori Ichikawa, Dai Kishida, Yasuhiro Shimojima, Ken-ei Sada, Jun Wada, David H. Thom, Noriaki Kurita

Arthritis Research & Therapy 26 ( 1 ) 2024.11

Histological differences related to autophagy in the minor salivary gland between primary and secondary types of Sjögren's syndrome. International journal

Hitomi Ono-Minagi, Tsutomu Nohno, Kiyofumi Takabatake, Takehiro Tanaka, Takayuki Katsuyama, Kohta Miyawaki, Jun Wada, Soichiro Ibaragi, Seiji Iida, Tadashi Yoshino, Hitoshi Nagatsuka, Takayoshi Sakai, Hideyo Ohuchi

BMC oral health 24 ( 1 ) 1099 - 1099 2024.9

Language：English Publishing type：Research paper (scientific journal)

Some forms of Sjögren's syndrome (SS) follow a clinical course accompanied by systemic symptoms caused by lymphocyte infiltration and proliferation in the liver, kidneys, and other organs. To better understand the clinical outcomes of SS, here we used minor salivary gland tissues from patients and examine their molecular, biological, and pathological characteristics. A retrospective study was performed, combining clinical data and formalin-fixed paraffin-embedded (FFPE) samples from female patients over 60 years of age who underwent biopsies at Okayama University Hospital. We employed direct digital RNA counting with nCounter® and multiplex immunofluorescence analysis with a PhenoCycler™ on the labial gland biopsies. We compared FFPE samples from SS patients who presented with other connective tissue diseases (secondary SS) with those from stable SS patients with symptoms restricted to the exocrine glands (primary SS). Secondary SS tissues showed enhanced epithelial damage and lymphocytic infiltration accompanied by elevated expression of autophagy marker genes in the immune cells of the labial glands. The close intercellular distance between helper T cells and B cells positive for autophagy-associated molecules suggests accelerated autophagy in these lymphocytes and potential B cell activation by helper T cells. These findings indicate that examination of FFPE samples from labial gland biopsies can be an effective tool for evaluating molecular histological differences between secondary and primary SS through multiplexed analysis of gene expression and tissue imaging.

DOI： 10.1186/s12903-024-04869-4

不全型Behcet病にみられた好中球浸潤を伴う急性尿細管間質性腎炎の一例

内田成彦, 田中景子, 三宅広将, 久保田菜月, 森本志帆, 志田原健太, 勝山隆行, 田邊克幸, 和田淳

日本腎臓学会誌 66 ( 6-W ) 1119 - 1119 2024.9

Successful treatment for life threatening recurrent non-traumatic rectus sheath hematoma in a case with microscopic polyangiitis with rapidly progressive glomerulonephritis.

Hiroyuki Nakanoh, Hidemi Takeuchi, Morimoto Shiho, Yuya Terajima, Shugo Okamoto, Yasuhiro Onishi, Keiko Tanaka, Takayuki Katsuyama, Kenji Tsuji, Yoshinori Matsumoto, Katsuyuki Tanabe, Hiroshi Morinaga, Mayu Uka, Koji Tomita, Haruhito A Uchida, Takao Hiraki, Jun Wada

Internal medicine (Tokyo, Japan) 2024.4

Language：English Publishing type：Research paper (scientific journal)

A 68-year-old woman was admitted to our hospital because of a rapid progression of renal dysfunction with positive myeloperoxidase antineutrophil cytoplasmic antibody and was diagnosed with rapidly progressive glomerulonephritis associated with microscopic polyangiitis (MPA). Severe right rectus sheath hematoma (RSH) bleeding from the inferior epigastric artery developed after starting hemodialysis, which required 4 transarterial embolizations due to recurrent bleeding. After additional treatment with methylprednisolone pulse therapy and rituximab, no rebleeding occurred. Although the giant hematoma reached the pelvis, it shrank spontaneously without any intervention. Nontraumatic RSH should therefore be considered when treating patients with multiple risk factors.

DOI： 10.2169/internalmedicine.3239-23

Discontinuity of care and trust in usual physician among patients with systemic lupus erythematosus

Katayama Yu, Miyawaki Yoshia, Shidahara Kenta, Nawachi Shoichi, Asano Yosuke, Katsuyama Eri, Katsuyama Takayuki, Takano-Narazaki Mariko, Matsumoto Yoshinori, Oguro Nao, Ishikawa Yuichi, Sakurai Natsuki, Hidekawa Chiharu, Ohno Shigeru, Ichikawa Takanori, Kishida Dai, Shimojima Yasuhiro, Sada Ken-ei, Wada Jun, Thom David, Kurita Noriaki† (†last author)

medRxiv 2024.03.13.24304255 2024.3

婦人科悪性腫瘍の摘出後,速やかにCKが正常化したHMGCR抗体陽性壊死性ミオパチーの一例

古山怜奈, 勝山恵理, 久保田菜月, 寺嶋悠也, 松本和也, 廣瀬啓, 志田原健太, 縄稚翔一, 中土井崇人, 片山祐, 宮脇義亜, 勝山隆行, 楢崎真理子, 松本佳則, 和田淳

日本リウマチ学会総会・学術集会プログラム・抄録集 68回 915 - 915 2024.3

Pseudo pseudo Meigs syndromeを呈したSLEの1例

中山菜々子, 片山祐, 久保田菜月, 寺嶋悠也, 松本和也, 廣瀬啓, 志田原健太, 縄稚翔一, 中土井崇人, 宮脇義亜, 勝山恵理, 勝山隆行, 楢崎真理子, 松本佳則, 和田淳

日本リウマチ学会総会・学術集会プログラム・抄録集 68回 914 - 914 2024.3

TAFRO症候群に緩徐進行1型糖尿病を合併した1例

喜舎場朝基, 片山祐, 久保田菜月, 寺嶋悠也, 松本和也, 廣瀬啓, 志田原健太, 縄稚翔一, 中土井崇人, 宮脇義亜, 勝山恵理, 勝山隆行, 楢崎真理子, 松本佳則, 和田淳

日本リウマチ学会総会・学術集会プログラム・抄録集 68回 914 - 914 2024.3

漿液性網膜剥離と蛋白漏出胃腸症を合併した全身性エリテマトーデスの一例

都明希, 勝山隆行, 久保田菜月, 寺嶋悠也, 松本和也, 廣瀬啓, 志田原健太, 縄稚翔一, 中土井崇人, 片山祐, 宮脇義亜, 勝山恵理, 楢崎真理子, 松本佳則, 和田淳

日本リウマチ学会総会・学術集会プログラム・抄録集 68回 914 - 914 2024.3

不全型ベーチェット病に急性尿細管間質性腎炎を合併した一例

有地萌音, 勝山恵理, 久保田菜月, 寺嶋悠也, 松本和也, 廣瀬啓, 志田原健太, 縄稚翔一, 中土井崇人, 片山祐, 宮脇義亜, 勝山隆行, 楢崎真理子, 松本佳則, 和田淳

日本リウマチ学会総会・学術集会プログラム・抄録集 68回 909 - 909 2024.3

好酸球性多発血管炎性肉芽腫症(EGPA)との鑑別に苦慮した好酸球性大腸炎(EoC)の一例

寺嶋悠也, 宮脇義亜, 久保田菜月, 松本和也, 廣瀬啓, 志田原健太, 中土井崇人, 縄稚翔一, 片山祐, 勝山恵理, 勝山隆行, 楢崎真理子, 松本佳則, 和田淳

日本リウマチ学会総会・学術集会プログラム・抄録集 68回 889 - 889 2024.3

重症感染症を合併した難治性中小型血管炎に対してアバコパンとγグロブリン大量静注療法(IVIG)で寛解導入に至った1例

小松原悠, 松本佳則, 久保田菜月, 寺嶋悠也, 松本和也, 廣瀬啓, 志田原健太, 縄稚翔一, 中土井崇人, 片山祐, 宮脇義亜, 勝山恵理, 勝山隆行, 楢崎真理子, 和田淳

日本リウマチ学会総会・学術集会プログラム・抄録集 68回 913 - 913 2024.3

骨免疫制御蛋白に着目した関節リウマチ病態形成メカニズムの解明

三前英恵, 松本佳則, 松本和也, 浅野洋介, 久保田菜月, 寺嶋悠也, 廣瀬啓, 縄稚翔一, 志田原健太, 中土井崇人, 片山祐, 宮脇義亜, 勝山恵理, 勝山隆行, 楢崎真理子, 和田淳

日本リウマチ学会総会・学術集会プログラム・抄録集 68回 910 - 910 2024.3

中小型血管炎:治療3 リツキシマブ1000mgの2回投与により寛解導入を行なった初発の顕微鏡的多発血管炎および多発血管炎性肉芽腫症の8例に関する記述研究

松本和也, 宮脇義亜, 久保田菜月, 寺嶋悠也, 廣瀬啓, 志田原健太, 中土井崇人, 縄稚翔一, 片山祐, 勝山隆行, 勝山恵理, 楢崎真理子, 松本佳則, 佐田憲映, 和田淳

日本リウマチ学会総会・学術集会プログラム・抄録集 68回 581 - 581 2024.3

上腸間膜動脈周囲軟部影から血管炎が疑われたが膵癌と判明した一例

志田原健太, 片山祐, 久保田菜月, 寺嶋悠也, 松本和也, 廣瀬啓, 中土井崇人, 縄稚翔一, 宮脇義亜, 勝山恵理, 勝山隆行, 楢崎真理子, 松本佳則, 和田淳

日本リウマチ学会総会・学術集会プログラム・抄録集 68回 881 - 881 2024.3

二次性の結節性多発動脈炎の発症したびまん性大細胞型B細胞性リンパ腫の一例

久保田菜月, 宮脇義亜, 寺嶋悠也, 松本和也, 廣瀬啓, 志田原健太, 中土井崇人, 縄稚翔一, 片山祐, 勝山隆行, 勝山恵理, 楢崎真理子, 松本佳則, 和田淳

日本リウマチ学会総会・学術集会プログラム・抄録集 68回 821 - 821 2024.3

The first presentation of a case of nail-patella syndrome newly diagnosed at the onset of rheumatoid arthritis: a case report. International journal

Kazuya Matsumoto, Yoshinori Matsumoto, Shoichi Nawachi, Yosuke Asano, Yu Katayama, Yoshia Miyawaki, Takayuki Katsuyama, Eri Katsuyama, Yoshihisa Nasu, Ken-Ei Sada, Jun Wada

BMC musculoskeletal disorders 25 ( 1 ) 139 - 139 2024.2

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Nail-patella syndrome (NPS) is a rare autosomal dominant disorder that is characterized by dysplasia of the nails, hypoplasia and/or dislocation of the patella and the presence of iliac horns. Using the CARE guidelines, we present the first reported case of NPS that was newly diagnosed at the onset of rheumatoid arthritis (RA). CASE PRESENTATION: A 74-year-old man was admitted to our hospital due to an 8-month history of arthralgia in bilateral wrists, elbows and fingers. He had a past history of glaucoma and left patella dislocation that had been operatively recentered at the age of 15 years. Laboratory data showed elevated levels of serum C-reactive protein and rheumatoid factor and an elevated titer of anti-SS-A antibodies, while estimated glomerular filtration rate (eGFR), titers of other antibodies and the results of a urinary test were normal. An X-ray showed deformity of bilateral radial heads and the right elbow, and magnetic resonance imaging (MRI) of his hands showed synovitis and erosion in the multiple swollen joints of the wrists and fingers. In addition to these typical features of RA, he had bilateral thumb nail dysplasia with mild hypoplasia of bilateral patellae and iliac horns as shown by the X-ray. He was diagnosed as having autosomal dominant disorder NPS co-existing with RA and he was treated with methotrexate in combination with an oral Janus kinase (JAK) inhibitor, leading to induction of remission. CONCLUSIONS: We have presented a rare case of NPS that was newly diagnosed at the onset of RA. Clinical and radiographic findings of NPS are highlighted in this case report for diagnosing NPS on the basis of typical manifestations.

DOI： 10.1186/s12891-024-07242-2

Infliximab biosimilar-induced lupus nephritis: A case report. Reviewed International journal

Kenta Shidahara, Takayuki Katsuyama, Kei Hirose, Kazuya Matsumoto, Shoichi Nawachi, Takato Nakadoi, Yosuke Asano, Yu Katayama, Yoshia Miyawaki, Eri Katsuyama, Mariko Takano-Narazaki, Yoshinori Matsumoto, Ken-Ei Sada, Jun Wada

Modern rheumatology case reports 2023.10

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

We present a case of microhematuria, proteinuria and hypocomplementemia that developed in a 55-year-old female who was being treated with an infliximab biosimilar (IFX-BS) for rheumatoid arthritis (RA). Renal biopsy showed lupus nephritis (ISN/RPS classification class IV+V). Treatment with the IFX-BS was discontinued, and treatment with prednisolone, hydroxychloroquine and abatacept was started, resulting in clinical remission of lupus nephritis and RA. Although tumor necrosis factor-α (TNF-α) inhibitors are known to induce production of autoantibodies, symptoms are usually limited to skin involvement or arthritis, and renal complications are rare. Physicians should be aware of the risk of lupus nephritis and carefully monitor patients for the development of renal involvement during treatment with TNF-α inhibitors.

DOI： 10.1093/mrcr/rxad061

病初期より関節リウマチの臨床像も有したリウマチ性多発筋痛症の一例

安藤航, 大塚勇輝, 副島佳晃, 川口満理奈, 大國皓平, 本多寛之, 長谷川功, 花山宜久, 勝山隆行, 大塚文男

日本病院総合診療医学会雑誌 19 ( 臨増2 ) 150 - 150 2023.8

病初期より関節リウマチの臨床像も有したリウマチ性多発筋痛症の一例

安藤航, 大塚勇輝, 副島佳晃, 川口満理奈, 大國皓平, 本多寛之, 長谷川功, 花山宜久, 勝山隆行, 大塚文男

日本病院総合診療医学会雑誌 19 ( 臨増2 ) 150 - 150 2023.8

Immunosuppressive Treatment for an anti-U1 Ribonucleoprotein Antibody-positive Patient with Pulmonary Arterial Hypertension: A Case Report. Reviewed

Kazuya Matsumoto, Yoshia Miyawaki, Takayuki Katsuyama, Takato Nakadoi, Kenta Shidahara, Kei Hirose, Shoichi Nawachi, Yosuke Asano, Yu Katayama, Eri Katsuyama, Mariko Takano-Narazaki, Yoshinori Matsumoto, Atsushi Mori, Satoshi Akagi, Ken-Ei Sada, Jun Wada

Internal medicine (Tokyo, Japan) 2023.7

Language：English Publishing type：Research paper (scientific journal)

A 34-year-old woman with pulmonary arterial hypertension (PAH) was admitted to the hospital. She had been diagnosed with PAH three years earlier and treated with triple vasodilator therapy. She was positive for anti-U1 ribonucleoprotein antibodies but did not show any other symptoms associated with autoimmune diseases. Corticosteroid and cyclophosphamide therapy was administered, suspecting the involvement of immunological pathophysiology. After 3 weeks, the mean pulmonary artery pressure decreased from 50 to 38 mmHg without any change in the vasodilators. Immunosuppressive therapy was effective in this patient with PAH with an anti-U1 ribonucleoprotein-antibody-positive response and might be an option for patients with these specific features.

DOI： 10.2169/internalmedicine.1407-22

The Association of Grit With Burnout Components (Professional Efficacy, Exhaustion, and Cynicism) Among Academic Rheumatologists: The TRUMP2-SLE Study. Reviewed International journal

Yoshia Miyawaki, Ken-Ei Sada, Kenta Shidahara, Shoichi Nawachi, Yosuke Asano, Yu Katayama, Keigo Hayashi, Eri Katsuyama, Takayuki Katsuyama, Mariko Takano-Narazaki, Yoshinori Matsumoto, Nao Oguro, Nobuyuki Yajima, Yuichi Ishikawa, Natsuki Sakurai, Chiharu Hidekawa, Ryusuke Yoshimi, Takanori Ichikawa, Dai Kishida, Yasuhiro Shimojima, Jun Wada, Noriaki Kurita

Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases 29 ( 6 ) 268 - 274 2023.5

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: There is a high prevalence of burnout among rheumatologists. Grit, which is defined as possessing perseverance and a passion to achieve long-term goals, is predictive of success in many professions; however, whether grit is associated with burnout remains unclear, especially among academic rheumatologists, who have multiple simultaneous responsibilities. Thus, the purpose of this study was to examine the associations between grit and self-reported burnout components-professional efficacy, exhaustion, and cynicism-in academic rheumatologists. METHODS: This cross-sectional study involved 51 rheumatologists from 5 university hospitals. The exposure was grit, measured using mean scores for the 8-item Short Grit Scale (range, 1-5 [5 = extremely high grit]). The outcome measures were mean scores for 3 burnout domains (exhaustion, professional efficacy, and cynicism; range, 1-6; measured using the 16-item Maslach Burnout Inventory-General Survey). General linear models were fitted with covariates (age, sex, job title [associate professor or higher vs lower], marital status, and having children). RESULTS: Overall, 51 physicians (median age, 45 years; interquartile range, 36-57; 76% men) were included. Burnout positivity was found in 68.6% of participants (n = 35/51; 95% confidence interval [CI], 54.1, 80.9). Higher grit was associated with higher professional efficacy (per 1-point increase; 0.51 point; 95% CI, 0.18, 0.84) but not with exhaustion or cynicism. Being male and having children were associated with lower exhaustion (-0.69; 95% CI, -1.28, -0.10; p = 0.02; and -0.85; 95% CI, -1.46, -0.24; p = 0.006). Lower job title (fellow or part-time lecturer) was associated with higher cynicism (0.90; 95% CI, 0.04, 1.75; p = 0.04). CONCLUSIONS: Grit is associated with higher professional efficacy among academic rheumatologists. To prevent burnout among staff, supervisors who manage academic rheumatologists should assess their staff's individual grit.

DOI： 10.1097/RHU.0000000000001989

Amelioration of nephritis in receptor for advanced glycation end-products (RAGE)-deficient lupus-prone mice through neutrophil extracellular traps. Reviewed International journal

Haruki Watanabe, Masataka Kubo, Akihiko Taniguchi, Yosuke Asano, Sumie Hiramatsu-Asano, Keiji Ohashi, Sonia Zeggar, Eri Katsuyama, Takayuki Katsuyama, Katsue Sunahori-Watanabe, Ken-Ei Sada, Yoshinori Matsumoto, Yasuhiko Yamamoto, Hiroshi Yamamoto, Myoungsun Son, Jun Wada

Clinical immunology (Orlando, Fla.) 250 109317 - 109317 2023.5

Language：English Publishing type：Research paper (scientific journal)

The receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor that regulates inflammation, cell migration, and cell fate. Systemic lupus erythematosus (SLE) is a chronic multiorgan autoimmune disease. To understand the function of RAGE in SLE, we generated RAGE-deficient (Ager-/-) lupus-prone mice by backcrossing MRL/MpJ-Faslpr/J (MRL-lpr) mice with Ager-/- C57BL/6 mice. In 18-week-old Ager-/- MRL-lpr, the weights of the spleen and lymph nodes, as well as the frequency of CD3+CD4-CD8- cells, were significantly decreased. Ager-/- MRL-lpr mice had significantly reduced urine albumin/creatinine ratios and markedly improved renal pathological scores. Moreover, neutrophil infiltration and neutrophil extracellular trap formation in the glomerulus were significantly reduced in Ager-/- MRL-lpr. Our study is the first to reveal that RAGE can have a pathologic role in immune cells, particularly neutrophils and T cells, in inflammatory tissues and suggests that the inhibition of RAGE may be a potential therapeutic strategy for SLE.

DOI： 10.1016/j.clim.2023.109317

Association of alcohol consumption and fatigue in SLE: A cross-sectional study from Lupus Registry of Nationwide Institution (LUNA) cohort. Reviewed International journal

Yu Katayama, Yoshia Miyawaki, Kenta Shidahara, Shoichi Nawachi, Yosuke Asano, Keiji Ohashi, Eri Katsuyama, Takayuki Katsuyama, Mariko Narazaki, Yoshinori Matsumoto, Ken-Ei Sada, Nobuyuki Yajima, Yasuhiro Shimojima, Ryusuke Yoshimi, Kunihiro Ichinose, Hiroshi Kajiyama, Michio Fujiwara, Shuzo Sato, Jun Wada

Lupus 32 ( 4 ) 9612033231159471 - 9612033231159471 2023.2

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: Fatigue is one of the most common complaints and is a potentially modifiable issue in systemic lupus erythematosus (SLE). Studies suggest that alcohol consumption has a protective effect against the development of SLE; however, an association between alcohol consumption and fatigue in patients with SLE has not been studied. Here, we assessed whether alcohol consumption was associated with fatigue using lupus patient-reported outcomes (LupusPRO). METHODS: This cross-sectional study, conducted between 2018 and 2019, included 534 patients (median age, 45 years; 87.3% female) from 10 institutions in Japan. The main exposure was alcohol consumption, which was defined as the frequency of drinking [<1 day/month (none group), ≤1 day/week (moderate group), and ≥2 days/week (frequent group)]. The outcome measure was the Pain Vitality domain score in LupusPRO. Multiple regression analysis was performed as the primary analysis after adjusting for confounding factors, such as age, sex, and damage. Subsequently, the same analysis was performed as a sensitivity analysis after multiple imputations (MIs) for missing data (n = 580). RESULTS: In total, 326 (61.0%) patients were categorized into the none group, 121 (22.7%) into the moderate group, and 87 (16.3%) into the frequent group. The frequent group was independently associated with less fatigue compared with none group [β = 5.98 (95% CI 0.19-11.76), p = 0.04], and the results did not substantially deviate after MI. CONCLUSIONS: Frequent drinking was associated with less fatigue, which highlights the need for further longitudinal studies focusing on drinking habits in patients with SLE.

DOI： 10.1177/09612033231159471

Pharmacologic inhibition of PARP5, but not that of PARP1 or 2, promotes cytokine production and osteoclastogenesis through different pathways. Reviewed International journal

Yosuke Asano, Yoshinori Matsumoto, Fang He, Takayuki Katsuyama, Eri Katsuyama, Shigetomo Tsuji, Hiroshi Kamioka, Jose La Rose, Robert Rottapel, Jun Wada

Clinical and experimental rheumatology 41 ( 9 ) 1735 - 1745 2023.1

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: PARPs, which are members of the poly(ADP-ribose) polymerase superfamily, promote tumorigenesis and tumour-associated inflammation and are thus therapeutic targets for several cancers. The aim of the present study is to investigate the mechanistic insight into the roles PARPs for inflammation. METHODS: Primary murine macrophages were cultured in the presence or absence of the PARP5 inhibitor NVP-TNKS656 to examine the role of PARP5 for cytokine production. RESULTS: In contrast to the roles of other PARPs for induction of inflammation, we found in the present study that pharmacologic inhibition of PARP5 induces production of inflammatory cytokines in primary murine macrophages. We found that treatment with the PARP5 inhibitor NVP-TNKS656 in macrophages enhanced steady-state and LPS-mediated cytokine production through degradation of IκBα and subsequent nuclear translocation of NF-κB. We also found that pharmacologic inhibition of PARP5 stabilises the adaptor protein 3BP2, a substrate of PARP5, and that accelerated cytokine production induced by PARP5 inhibition was rescued in 3BP2-deleted macrophages. Additionally, we found that LPS increases the expression of 3BP2 and AXIN1, a negative regulator of β-catenin, through suppression of PARP5 transcripts in macrophages, leading to further activation of cytokine production and inhibition of β-catenin-mediated cell proliferation, respectively. Lastly, we found that PARP5 inhibition in macrophages promotes osteoclastogenesis through stabilisation of 3BP2 and AXIN1, leading to activation of SRC and suppression of β-catenin, respectively. CONCLUSIONS: Our results show that pharmacologic inhibition of PARP5 against cancers unexpectedly induces adverse autoinflammatory side effects through activation of innate immunity, unlike inhibition of other PARPs.

DOI： 10.55563/clinexprheumatol/qf55h8

A case of sitosterolaemia-caused systemic large-vessel stenosis mimicking Takayasu arteritis in which FDG-PET provided a clue for the differential diagnosis Reviewed

Takato Nakadoi, Eri Katsuyama, Kazuya Matsumoto, Kenta Shidahara, Kei Hirose, Shoichi Nawachi, Yosuke Asano, Yu Katayama, Yoshia Miyawaki, Takayuki Katsuyama, Mariko Takano-Narazaki, Yoshinori Matsumoto, Ken-Ei Sada, Hayato Tada, Jun Wada

Rheumatology Advances in Practice 7 ( 3 ) 2023.1

Cytokine and chemokine multiplex analysis-based exploration for potential treatment and prognostic prediction in large-vessel vasculitis: A preliminary observational study Reviewed International journal

Nobuya Abe, Michihiro Kono, Takayuki Katsuyama, Kazumasa Ohmura, Taiki Sato, Kohei Karino, Yuichiro Fujieda, Masaru Kato, Rie Hasebe, Masaaki Murakami, Tatsuya Atsumi

Frontiers Immunology 13 1066916 - 1066916 2022.11

Language：English Publishing type：Research paper (scientific journal)

Large-vessel vasculitis (LVV) is subclassified into two phenotypes; Takayasu arteritis and giant cell arteritis. Although the pathogenesis of LVV is not fully established, IL-6-IL-17 axis and IL-12-IFN-γ axis play critical roles in the disease development. We aimed to clarify the association between the disease state and cytokine/chemokine levels, to assess disease course as prognosis and to predict regulators in patients with LVV using the blood profiles of multiple cytokines/chemokines. This retrospective analysis comprised 35 LVV patients whose blood were collected, and multiplex cytokine/chemokine analysis with 28 analytes was performed. The differences of cytokines/chemokines corresponding disease status, upstream regulator analysis, pathway analysis and cluster analysis were conducted using the cytokines/chemokines profile. Relapse-free survival rate was calculated with Kaplan-Meier analysis in the classified clusters. In the robust analysis, IL-4, CCL2/MCP-1, TNFSF13/APRIL, TNFSF13B/BAFF, CHI3L1 and VEGF-A levels were significantly changed after treatment. Untreated LVV patients demonstrated activation of NFκB-related molecules and these patients are potentially treated with JAK/STAT inhibitors, anti-TNF-α inhibitors and IL-6 inhibitors. Cluster analysis in active LVV patients revealed two clusters including one with high blood levels of IL-1β, IL-6, IL-17, IL-23 and CCL20/MIP-3. A subgroup of the LVV patients showed activated IL-17 signature with high relapse frequency, and JAK/TyK2 inhibitors and IFN-γ inhibitors were detected as potentially upstream inhibitors. Blood cytokine/chemokine profiles would be useful for prediction of relapse and potentially contributes to establish therapeutic strategy as precision medicine in LVV patients.

DOI： 10.3389/fimmu.2022.1066916.

A case of neuro‐Behcet's disease preceded by cellulitis‐like cutaneous arteritis and multiple pharyngeal ulcers Reviewed International journal

Emi Yokoyama, Yoshio Kawakami, Takayuki Katsuyama, Hidenori Marunaka, Shin Morizane

International Journal of Dermatology 2022.10

Grit personality of physicians and achievement of treatment goals in patients with systemic lupus erythematosus. Reviewed International journal

Ken-Ei Sada, Yoshia Miyawaki, Kenta Shidahara, Shoichi Nawachi, Yu Katayama, Yosuke Asano, Keigo Hayashi, Keiji Ohashi, Eri Katsuyama, Takayuki Katsuyama, Mariko Takano-Narazaki, Yoshinori Matsumoto, Nao Oguro, Yuichi Ishikawa, Natsuki Sakurai, Chiharu Hidekawa, Ryusuke Yoshimi, Dai Kishida, Takanori Ichikawa, Yasuhiro Shimojima, Noriaki Kurita, Nobuyuki Yajima

Rheumatology (Oxford, England) 62 ( 6 ) 2154 - 2159 2022.10

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: Although personality characteristics of patients with systemic lupus erythematosus (SLE) affect their disease activity and damage, it is unclear whether those of attending physicians affect the outcomes of patients with SLE. Grit is a personality trait for achieving long-term goals that may influence the decision-making for continuing treatment plans for patients. We aimed to evaluate the relationship between the grit of attending physicians and achievement of treatment goals in patients with SLE. METHODS: This cross-sectional study was conducted at five referral hospitals. The main exposure was "consistency of interest" and "perseverance of effort" of the attending physicians, measured by the Short Grit Scale. The primary outcome was achievement of a lupus low disease activity state (LLDAS). The association between physicians' grit score and LLDAS was analyzed by generalized estimating equation (GEE) logistic regression with cluster robust variance estimation with adjustment for confounders. RESULTS: The median (interquartile range) total, consistency, and perseverance scores of 37 physicians were 3.1 (2.9-3.6), 3.3 (2.8-3.8), and 3.3 (3.0-3.5), respectively. Among the 386 patients, 154 (40%) had achieved LLDAS. Low consistency score (≤2.75) in physicians was related to LLDAS achievement independently using GEE logistic regression. The score of the question "I often set a goal but later choose to pursue a different one" was significantly higher in patients achieving LLDAS. CONCLUSIONS: Difficulty of attending physicians to change treatment goals might be related to lower LLDAS achievement in patients with SLE.

DOI： 10.1093/rheumatology/keac612

Association of one-point glucocorticoid-free status with chronic damage and disease duration in systemic lupus erythematosus: a cross-sectional study. Reviewed International journal

Ken-Ei Sada, Yu Katayama, Yosuke Asano, Keigo Hayashi, Yoshia Miyawaki, Keiji Ohashi, Eri Katsuyama, Takayuki Katsuyama, Mariko Takano-Narazaki, Yoshinori Matsumoto, Ryusuke Yoshimi, Yasuhiro Shimojima, Shigeru Ohno, Hiroshi Kajiyama, Kunihiro Ichinose, Shuzo Sato, Michio Fujiwara, Nobuyuki Yajima

Lupus science & medicine 9 ( 1 ) 2022.9

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: It is still unclear how glucocorticoids (GCs) affect the long-term clinical course of patients with SLE. The objective of this study is to explore the factors associated with GC-free treatment status. METHODS: Using data from the lupus registry of nationwide institutions, GC dose at registration was compared between short, middle and long disease durations of <5, 5-20 and ≥20 years, respectively. After excluding patients who never used GC, we evaluated the relationship between GC-free status and chronic damage using Systemic Lupus International Collaborating Clinics Damage Index. RESULTS: GC doses at enrolment of the 1019 patients were as follows: GC-free in 101 (10%); 0<prednisolone (PSL) ≤5 mg/day in 411 (40%); 5<PSL ≤7.5 in 169 (17%); 7.5<PSL ≤10 in 194 (19%) and PSL≥10 in 144 (14%) patients. Of the patients who were not currently using GCs, patients who never used GC more frequently had short disease duration (66% with short, 23% with middle and 17% with long disease duration, p=0.00029). Univariate analysis of patients who underwent GC treatment showed that patients without GCs exhibited older age, lower disease activity, less immunosuppressant and hydroxychloroquine use and higher C3 levels. Among patients with a disease duration of ≥20 years, GC-free status was more frequent in patients without chronic damage (11% vs 4%, p=0.023). After adjusting for age, sex and disease activity, no chronic damage accrual was associated with GC-free status (OR 3.6, 95% CI 1.1 to 11.3). CONCLUSION: Even in the patients with long disease duration, one-point GC-free treatment status might be related to no chronic damage accrual.

DOI： 10.1136/lupus-2022-000772

Two Cases of Rheumatoid Arthritis with Cuataneous Leukocytoclastic Vasculitis Induced by Tocilizumab

Mana USUI, Emi YOKOYAMA, Osamu YAMASAKI, Takayuki KATSUYAMA, Miyuki KOSOGABE, Yoshinori SHIRAFUJI, Shin MORIZANE

Nishi Nihon Hifuka 84 ( 3 ) 202 - 206 2022.6

A case of recurrent IgG4-related disease successfully treated with belimumab after remission of systemic lupus erythematosus. Reviewed International journal

Yu Katayama, Takayuki Katsuyama, Kenta Shidahara, Shoichi Nawachi, Yosuke Asano, Keiji Ohashi, Yoshia Miyawaki, Eri Katsuyama, Mariko Narazaki, Yoshinori Matsumoto, Ken-Ei Sada, Jun Wada

Rheumatology (Oxford, England) 61 ( 10 ) e308-e310 2022.5

Tankyrase represses autoinflammation through the attenuation of TLR2 signaling. Reviewed International journal

Yoshinori Matsumoto, Ioannis D Dimitriou, Jose La Rose, Melissa Lim, Susan Camilleri, Napoleon Law, Hibret A Adissu, Jiefei Tong, Michael F Moran, Andrzej Chruscinski, Fang He, Yosuke Asano, Takayuki Katsuyama, Ken-Ei Sada, Jun Wada, Robert Rottapel

The Journal of clinical investigation 132 ( 7 ) 2022.4

Language：English Publishing type：Research paper (scientific journal)

Dysregulation of Toll-like receptor (TLR) signaling contributes to the pathogenesis of autoimmune diseases. Here, we provide genetic evidence that tankyrase, a member of the poly(ADP-ribose) polymerase (PARP) family, negatively regulates TLR2 signaling. We show that mice lacking tankyrase in myeloid cells developed severe systemic inflammation with high serum inflammatory cytokine levels. We provide mechanistic evidence that tankyrase deficiency resulted in tyrosine phosphorylation and activation of TLR2 and show that phosphorylation of tyrosine 647 within the TIR domain by SRC and SYK kinases was critical for TLR2 stabilization and signaling. Last, we show that the elevated cytokine production and inflammation observed in mice lacking tankyrase in myeloid cells were dependent on the adaptor protein 3BP2, which is required for SRC and SYK activation. These data demonstrate that tankyrase provides a checkpoint on the TLR-mediated innate immune response.

DOI： 10.1172/JCI140869

痛風性関節炎、特発性間質性肺炎発症後に多発脳梗塞を呈した顕微鏡的多発血管炎(MPA)の1例

堀口裕紀, 松本佳則, 松本和也, 廣瀬啓, 志田原健太, 縄稚翔一, 中土井崇人, 浅野洋介, 片山祐, 宮脇義亜, 勝山恵理, 勝山隆行, 楢崎真理子, 佐田憲映, 和田淳

日本リウマチ学会総会・学術集会プログラム・抄録集 66回 756 - 756 2022.3

初発から40年後に診断に至った炎症症候持続TNF受容体関連周期性症候群の一例

高嶋香菜子, 松本佳則, 松本和也, 廣瀬啓, 志田原健太, 縄稚翔一, 中土井崇人, 浅野洋介, 片山祐, 大橋敬司, 宮脇義亜, 勝山恵理, 勝山隆行, 楢崎真理子, 佐田憲映, 和田淳

日本リウマチ学会総会・学術集会プログラム・抄録集 66回 756 - 756 2022.3

大型血管炎が疑われた大動脈周囲悪性リンパ腫の1例

道廣麻友, 勝山隆行, 松本和也, 廣瀬啓, 志田原健太, 縄稚翔一, 中土井崇人, 浅野洋介, 片山祐, 大橋敬司, 宮脇義亜, 勝山恵理, 楢崎真理子, 佐田憲映, 松本佳則, 和田淳

日本リウマチ学会総会・学術集会プログラム・抄録集 66回 756 - 756 2022.3

IgG4関連肥厚性硬膜炎に重篤な視力障害を来たし視神経周囲炎が示唆された一例 Reviewed

上舞直, 宮脇義亜, 松本和也, 中土井崇人, 大橋敬司, 廣瀬啓, 縄稚翔一, 志田原健太, 浅野洋介, 片山祐, 勝山恵理, 勝山隆行, 楢崎真理子, 松本佳則, 佐田憲映, 和田淳

日本リウマチ学会総会・学術集会プログラム・抄録集 66回 754 - 754 2022.3

爪形成不全と肘関節脱臼を伴った関節リウマチの1例

増田倫敦, 松本佳則, 松本和也, 廣瀬啓, 志田原健太, 縄稚翔一, 中土井崇人, 浅野洋介, 片山祐, 大橋敬司, 宮脇義亜, 勝山恵理, 勝山隆行, 楢崎真理子, 佐田憲映, 和田淳

日本リウマチ学会総会・学術集会プログラム・抄録集 66回 754 - 754 2022.3

関節リウマチの増悪との鑑別に苦慮した両側踵脆弱性骨折の1例

氏家正皓, 片山祐, 松本和也, 廣瀬啓, 志田原健太, 縄稚翔一, 中土井崇人, 浅野洋介, 大橋敬司, 宮脇義亜, 勝山恵理, 勝山隆行, 楢崎真理子, 佐田憲映, 松本佳則, 中原龍一, 那須義久, 西田圭一郎, 和田淳

日本リウマチ学会総会・学術集会プログラム・抄録集 66回 753 - 753 2022.3

CD30-targeted therapy induces apoptosis of inflammatory cytokine-stimulated synovial fibroblasts and ameliorates collagen antibody-induced arthritis in mice. Reviewed International journal

Minami Matsuhashi, Keiichiro Nishida, Misa Sakamoto, Yuka Gion, Aki Yoshida, Takayuki Katsuyama, Ryuichi Nakahara, Yoshihisa Nasu, Yoshinori Matsumoto, Yasuharu Sato, Toshifumi Ozaki

Inflammation research : official journal of the European Histamine Research Society ... [et al.] 71 ( 2 ) 215 - 226 2022.2

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: It has been reported that levels of soluble CD30 in serum and joint fluid are significantly elevated in patients with rheumatoid arthritis (RA). This study aimed to investigate whether CD30 could be a therapeutic target for RA. METHODS: The expression and localization of CD30 were examined by immunohistochemical and double immunofluorescence staining on synovial tissue samples obtained from patients with RA or osteoarthritis (OA) during surgery. Changes in CD30 expression of fibroblast-like synoviocytes (FLS) from RA patients with or without TNFα and IL-1β stimulation were examined by the polymerase chain reaction (PCR) and flow cytometry. Collagen antibody-induced arthritis (CAIA) was created in DBA/1 mice, and the therapeutic effect of brentuximab vedotin (BV) was examined by clinical score, histological findings and measurement of serum levels of SAA, IL-6, and TNFα. RESULTS: CD30 expression was significantly higher in samples from patients with RA than from those with OA. Double immunofluorescence showed a low rate of co-localization of CD30 with CD20 or CD90, but a high rate of co-localization of CD30 and CD138. CD30 mRNA expression was upregulated 11.7-fold in FLS following stimulation by inflammatory cytokines. The clinical scores of CAIA mice were significantly lower following both BV treatments, however, the histological scores of CAIA mice were significantly lower only following treatment with high dose BV (70 mg/kg). CONCLUSIONS: CD30 was expressed on immunocompetent cells in synovial tissue from RA patients and in cytokine-stimulated FLS in vitro. High dose BV (70 mg/kg) showed significant therapeutic effects in ameliorating inflammation and joint destruction in CAIA mice, but low dose BV (30 mg/kg) was insufficient.

DOI： 10.1007/s00011-021-01537-z

Real-world data on vitamin D supplementation and its impacts in systemic lupus erythematosus: Cross-sectional analysis of a lupus registry of nationwide institutions (LUNA). Reviewed International journal

Keigo Hayashi, Ken-Ei Sada, Yosuke Asano, Yu Katayama, Keiji Ohashi, Michiko Morishita, Yoshia Miyawaki, Haruki Watanabe, Takayuki Katsuyama, Mariko Narazaki, Yoshinori Matsumoto, Nobuyuki Yajima, Ryusuke Yoshimi, Yasuhiro Shimojima, Shigeru Ohno, Hiroshi Kajiyama, Kunihiro Ichinose, Shuzo Sato, Michio Fujiwara, Jun Wada

PloS one 17 ( 6 ) e0270569 2022

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Although vitamin D concentration is reportedly associated with the pathogenesis and pathology of systemic lupus erythematosus (SLE), benefits of vitamin D supplementation in SLE patients have not been elucidated, to our knowledge. We investigated the clinical impacts of vitamin D supplementation in SLE. METHODS: A cross-sectional analysis was performed using data from a lupus registry of nationwide institutions. We evaluated vitamin D supplementation status associated with disease-related Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) as a parameter of long-term disease activity control. RESULTS: Of the enrolled 870 patients (mean age: 45 years, mean disease duration: 153 months), 426 (49%) received vitamin D supplementation. Patients with vitamin D supplementation were younger (43.2 vs 47.5 years, P < 0.0001), received higher doses of prednisolone (7.6 vs 6.8 mg/day, P = 0.002), and showed higher estimated glomerular filtration rates (79.3 vs 75.3 mL/min/1.73m2, P = 0.02) than those without supplementation. Disease-related SDI (0.73 ± 1.12 vs 0.73 ± 1.10, P = 0.75), total SDI, and SLE Disease Activity Index (SLEDAI) did not significantly differ between patients receiving and not receiving vitamin D supplementation. Even after excluding 136 patients who were highly recommended vitamin D supplementation (with age ≥ 75 years, history of bone fracture or avascular necrosis, denosumab use, and end-stage renal failure), disease-related SDI, total SDI, and SLEDAI did not significantly differ between the two groups. CONCLUSIONS: Even with a possible Vitamin D deficiency and a high risk of bone fractures in SLE patients, only half of our cohort received its supplementation. The effect of vitamin D supplementation for disease activity control was not observed.

DOI： 10.1371/journal.pone.0270569

An Elderly Male with Primary Sjögren's Syndrome Presenting Pleuritis as the Initial Manifestation. Reviewed

Yukichika Yamamoto, Yuki Otsuka, Takayuki Katsuyama, Yoshito Nishimura, Kosuke Oka, Kou Hasegawa, Hideharu Hagiya, Fumio Otsuka

Acta medica Okayama 75 ( 4 ) 539 - 542 2021.8

Language：English Publishing type：Research paper (scientific journal)

Primary Sjögren's syndrome (SS) is an autoimmune disease that usually affects the exocrine glands in mid-dle-aged women. Fifteen percent of SS patients experience severe systemic extraglandular complications, and pleuritis is one of the rare complications of SS. We report the case of an elderly Japanese man who initially pre-sented with a prolonged fever and chest pain and was finally diagnosed with primary SS-associated pleuritis. Of the nine reported cases of primary SS that initially presented with pleuritis, up to six cases were elderly males. This case highlights the complication of pleuritis among elderly males with primary SS.

DOI： 10.18926/AMO/62409

Splicing factor SRSF1 is indispensable for regulatory T cell homeostasis and function. Reviewed International journal

Takayuki Katsuyama, Vaishali R Moulton

Cell reports 36 ( 1 ) 109339 - 109339 2021.7

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

The ability of regulatory T (Treg) cells to control the immune response and limit the development of autoimmune diseases is determined by distinct molecular processes, which are not fully understood. We show here that serine/arginine-rich splicing factor 1 (SRSF1), which is decreased in T cells from patients with systemic lupus erythematosus, is necessary for the homeostasis and proper function of Treg cells, because its conditional absence in these cells leads to profound autoimmunity and organ inflammation by elevating the glycolytic metabolism and mTORC1 activity and the production of proinflammatory cytokines. Our data reveal a molecular mechanism that controls Treg cell plasticity and offer insights into the pathogenesis of autoimmune disease.

DOI： 10.1016/j.celrep.2021.109339

Endonuclease increases efficiency of osteoblast isolation from murine calvariae. Reviewed International journal

Yosuke Asano, Yoshinori Matsumoto, Jose La Rose, Fang He, Takayuki Katsuyama, Wang Ziyi, Shigetomo Tsuji, Hiroshi Kamioka, Robert Rottapel, Jun Wada

Scientific reports 11 ( 1 ) 8502 - 8502 2021.4

Language：English Publishing type：Research paper (scientific journal)

Bone is a highly dynamic organ that undergoes remodeling equally regulated by osteoblast-mediated bone formation and osteoclast-mediated bone resorption. To clarify the regulation of osteoblastogenesis, primary murine osteoblasts are required for an in vitro study. Primary osteoblasts are isolated from neonatal calvariae through digestion with collagenase. However, the number of cells collected from one pup is not sufficient for further in vitro experiments, leading to an increase in the use of euthanized pups. We hypothesized that the viscosity of digested calvariae and digestion solution supplemented with collagenase results in cell clumping and reduction of isolated cells from bones. We simply added Benzonase, a genetically engineered endonuclease that shears all forms of DNAs/RNAs, in order to reduce nucleic acid-mediated viscosity. We found that addition of Benzonase increased the number of collected osteoblasts by three fold compared to that without Benzonase through reduction of viscosity. Additionally, Benzonase has no effect on cellular identity and function. The new osteoblast isolation protocol with Benzonase minimizes the number of neonatal pups required for an in vitro study and expands the concept that isolation of other populations of cells including osteocytes that are difficult to be purified could be modified by Benzonase.

DOI： 10.1038/s41598-021-87716-8

Splicing factor SRSF1 limits IFN-γ production via RhoH and ameliorates experimental nephritis. Reviewed International journal

Takayuki Katsuyama, Hao Li, Suzanne M Krishfield, Vasileios C Kyttaris, Vaishali R Moulton

Rheumatology (Oxford, England) 60 ( 1 ) 420 - 429 2021.1

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: CD4 T helper 1 (Th1) cells producing IFN-γ contribute to inflammatory responses in the pathogenesis of SLE and lupus nephritis. Moreover, elevated serum type II IFN levels precede the appearance of type I IFNs and autoantibodies in patient years before clinical diagnosis. However, the molecules and mechanisms that control this inflammatory response in SLE remain unclear. Serine/arginine-rich splicing factor 1 (SRSF1) is decreased in T cells from SLE patients, and restrains T cell hyperactivity and systemic autoimmunity. Our objective here was to evaluate the role of SRSF1 in IFN-γ production, Th1 differentiation and experimental nephritis. METHODS: T cell-conditional Srsf1-knockout mice were used to study nephrotoxic serum-induced nephritis and evaluate IFN-γ production and Th1 differentiation by flow cytometry. RNA sequencing was used to assess transcriptomics profiles. RhoH was silenced by siRNA transfections in human T cells by electroporation. RhoH and SRSF1 protein levels were assessed by immunoblots. RESULTS: Deletion of Srsf1 in T cells led to increased Th1 differentiation and exacerbated nephrotoxic serum nephritis. The expression levels of RhoH are decreased in Srsf1-deficient T cells, and silencing RhoH in human T cells leads to increased production of IFN-γ. Furthermore, RhoH expression was decreased and directly correlated with SRSF1 in T cells from SLE patients. CONCLUSION: Our study uncovers a previously unrecognized role of SRSF1 in restraining IFN-γ production and Th1 differentiation through the control of RhoH. Reduced expression of SRSF1 may contribute to pathogenesis of autoimmune-related nephritis through these molecular mechanisms.

DOI： 10.1093/rheumatology/keaa300

Corrigendum: RUNX2 Phosphorylation by Tyrosine Kinase ABL Promotes Breast Cancer Invasion. International journal

Fang He, Yoshinori Matsumoto, Yosuke Asano, Yuriko Yamamura, Takayuki Katsuyama, Jose La Rose, Nahoko Tomonobu, Ni Luh Gede Yoni Komalasari, Masakiyo Sakaguchi, Robert Rottapel, Jun Wada

Frontiers in oncology 11 729192 - 729192 2021

RUNX2 Phosphorylation by Tyrosine Kinase ABL Promotes Breast Cancer Invasion. International journal

Fang He, Yoshinori Matsumoto, Yosuke Asano, Yuriko Yamamura, Takayuki Katsuyama, Jose La Rose, Nahoko Tomonobu, Ni Luh Gede Yoni Komalasari, Masakiyo Sakaguchi, Robert Rottapel, Jun Wada

Frontiers in oncology 11 665273 - 665273 2021

Language：English Publishing type：Research paper (scientific journal)

Activity of transcription factors is normally regulated through interaction with other transcription factors, chromatin remodeling proteins and transcriptional co-activators. In distinction to these well-established transcriptional controls of gene expression, we have uncovered a unique activation model of transcription factors between tyrosine kinase ABL and RUNX2, an osteoblastic master transcription factor, for cancer invasion. We show that ABL directly binds to, phosphorylates, and activates RUNX2 through its SH2 domain in a kinase activity-dependent manner and that the complex formation of these proteins is required for expression of its target gene MMP13. Additionally, we show that the RUNX2 transcriptional activity is dependent on the number of its tyrosine residues that are phosphorylated by ABL. In addition to regulation of RUNX2 activity, we show that ABL transcriptionally enhances RUNX2 expression through activation of the bone morphogenetic protein (BMP)-SMAD pathway. Lastly, we show that ABL expression in highly metastatic breast cancer MDA-MB231 cells is associated with their invasive capacity and that ABL-mediated invasion is abolished by depletion of endogenous RUNX2 or MMP13. Our genetic and biochemical evidence obtained in this study contributes to a mechanistic insight linking ABL-mediated phosphorylation and activation of RUNX2 to induction of MMP13, which underlies a fundamental invasive capacity in cancer and is different from the previously described model of transcriptional activation.

DOI： 10.3389/fonc.2021.665273

Splicing factor SRSF1 controls T cell homeostasis and its decreased levels are linked to lymphopenia in systemic lupus erythematosus. Reviewed International journal

Takayuki Katsuyama, Ignacio Juarez Martin-Delgado, Suzanne M Krishfield, Vasileios C Kyttaris, Vaishali R Moulton

Rheumatology (Oxford, England) 59 ( 8 ) 2146 - 2155 2020.8

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: Lymphopenia is a frequent clinical manifestation and risk factor for infections in SLE, but the underlying mechanisms are not fully understood. We previously identified novel roles for the RNA-binding protein serine arginine-rich splicing factor 1 (SRSF1) in the control of genes involved in signalling and cytokine production in human T cells. SRSF1 is decreased in T cells from patients with SLE and associates with severe disease. Because SRSF1 controls the expression of apoptosis-related genes, we hypothesized that SRSF1 controls T cell homeostasis and, when reduced, leads to lymphopenia. METHODS: We evaluated SRSF1 expression in T cells from SLE patients by immunoblots and analysed its correlation with clinical parameters. T cell conditional Srsf1 knockout mice were used to evaluate lymphoid cells and apoptosis by flow cytometry. Quantitative PCR and immunoblots were used to assess Bcl-xL mRNA and protein expression. SRSF1 overexpression was performed by transient transfections by electroporation. RESULTS: We found that low SRSF1 levels correlated with lymphopenia in SLE patients. Selective deletion of Srsf1 in T cells in mice led to T cell lymphopenia, with increased apoptosis and decreased expression of the anti-apoptotic Bcl-xL. Lower SRSF1 expression correlated with low Bcl-xL levels in T cells and lower Bcl-xL levels associated with lymphopenia in SLE patients. Importantly, overexpression of SRSF1 rescued survival of T cells from patients with SLE. CONCLUSION: Our studies uncovered a previously unrecognized role for SRSF1 in the control of T cell homeostasis and its reduced expression as a molecular defect that contributes to lymphopenia in systemic autoimmunity.

DOI： 10.1093/rheumatology/keaa094

Association of explanatory histological findings and urinary protein and serum creatinine levels at renal biopsy in lupus nephritis: a cross-sectional study. Reviewed International journal

Eri Katsuyama, Yoshia Miyawaki, Ken-Ei Sada, Yosuke Asano, Keigo Hayashi, Yuriko Yamamura, Sumie Hiramatsu-Asano, Michiko Morishita, Keiji Ohashi, Haruki Watanabe, Takayuki Katsuyama, Mariko Narazaki, Yoshinori Matsumoto, Jun Wada

BMC nephrology 21 ( 1 ) 208 - 208 2020.6

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The aim of the present study was to evaluate the association between the histology of active and chronic lesions and urinary protein and serum creatinine (SCr) levels, as common clinical endpoints in clinical trials for lupus nephritis (LN). METHODS: In total, 119 patients diagnosed with LN class III, IV, and V, as defined by the International Society of Nephrology/Renal Pathology Society, between 1990 and 2015, were enrolled in the present study. Multiple regression analysis was performed to explore semi-quantitative histological variables associated with urinary protein and SCr levels. RESULTS: The mean age of the enrolled patients was 45 years, and 79% were female. The mean SCr and mean urinary protein levels at the time of renal biopsy were 0.87 mg/dl and 3.00 g/gCr, respectively. Class IV (71%) was the most common type of LN followed by class III (17%), and class V (13%). Multicollinearity was confirmed between monocellular infiltration (variance inflation factor [VIF] = 10.22) and interstitial fibrosis (VIF = 10.29), and between karyorrhexis (VIF = 4.14) and fibrinoid necrosis (VIF = 4.29). Fibrinoid necrosis and monocellular infiltration were subsequently excluded, and multiple regression analysis revealed that only the urinary protein level was correlated with wire loop lesions (β-coefficient [β]: 1.09 and confidence interval [CI]: 0.35 to 1.83), and that the SCr level was correlated with glomerular sclerosis (β: 1.08 and CI: 0.43 to 1.74). CONCLUSION: As urinary protein and SCr levels were not quantitatively associated with active lesions, they may not accurately reflect the response to remission induction therapy in patients with LN.

DOI： 10.1186/s12882-020-01868-9

Splicing factor SRSF1 controls T cell hyperactivity and systemic autoimmunity. Reviewed International journal

Takayuki Katsuyama, Hao Li, Denis Comte, George C Tsokos, Vaishali R Moulton

The Journal of clinical investigation 129 ( 12 ) 5411 - 5423 2019.12

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

Systemic lupus erythematosus (SLE) is a devastating autoimmune disease in which hyperactive T cells play a critical role. Understanding molecular mechanisms underlying the T cell hyperactivity will lead to identification of specific therapeutic targets. Serine/arginine-rich splicing factor 1 (SRSF1) is an essential RNA-binding protein that controls posttranscriptional gene expression. We have demonstrated that SRSF1 levels are aberrantly decreased in T cells from patients with SLE and that they correlate with severe disease, yet the role of SRSF1 in T cell physiology and autoimmune disease is largely unknown. Here we show that T cell-restricted Srsf1-deficient mice develop systemic autoimmunity and lupus-nephritis. Mice exhibit increased frequencies of activated/effector T cells producing proinflammatory cytokines, and an elevated T cell activation gene signature. Mechanistically, we noted increased activity of the mechanistic target of rapamycin (mTOR) pathway and reduced expression of its repressor PTEN. The mTOR complex 1 (mTORC1) inhibitor rapamycin suppressed proinflammatory cytokine production by T cells and alleviated autoimmunity in Srsf1-deficient mice. Of direct clinical relevance, PTEN levels correlated with SRSF1 in T cells from patients with SLE, and SRSF1 overexpression rescued PTEN and suppressed mTORC1 activation and proinflammatory cytokine production. Our studies reveal the role of a previously unrecognized molecule, SRSF1, in restraining T cell activation, averting the development of autoimmune disease, and acting as a potential therapeutic target for lupus.

DOI： 10.1172/JCI127949

Cluster Analysis Using Anti-Aminoacyl-tRNA Synthetases and SS-A/Ro52 antibodies in Patients With Polymyositis/Dermatomyositis. Reviewed International journal

Keiji Ohashi, Ken-Ei Sada, Yu Nakai, Shun Matsushima, Yosuke Asano, Keigo Hayashi, Yuriko Yamamura, Sumie Hiramatsu, Yoshia Miyawaki, Michiko Morishita, Takayuki Katsuyama, Eri Katsuyama, Haruki Watanabe, Noriko Tatebe, Mariko Narazaki, Yoshinori Matsumoto, Katsue Sunahori Watanabe, Tomoko Kawabata, Jun Wada

Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases 25 ( 6 ) 246 - 251 2019.9

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: Although several autoantibodies have been identified for polymyositis/dermatomyositis (PM/DM) diagnosis, the clinical impact of these antibodies is yet to be elucidated. METHODS: Patients with PM/DM at Okayama University Hospital from 2012 to 2016 were historically enrolled, and antibody profiles were analyzed using line immunoassay. Hierarchical cluster analysis was performed based on serological analysis of anti-aminoacyl-tRNA synthetase (ARS) antibodies, including anti-Jo-1, PL-7, PL-12, EJ, OJ, and SS-A/Ro-52 antibodies. Clinical symptoms and relapse proportions were compared among these clusters. RESULTS: Sixty-one patients were enrolled in this study: 28 were diagnosed with PM, and 33 were diagnosed with DM. The following 3 clusters were determined: 1 (n = 10), anti-Jo-1 and anti-SS-A/Ro-52 antibodies double positive (10/10, 100%); 2 (n = 24), anti-SS-A/Ro-52 antibody positive (20/24, 83%), anti-Jo-1 antibody negative (24/24, 100%), and anti-ARS antibodies (excluding anti-Jo-1 antibody) positive (15/24, 63%); and 3 (n = 27), anti-Jo-1 and anti-SS-A/Ro52 antibodies double negative (26/27, 96%). The proportion of patients who relapsed was significantly lower in cluster 3 than it was in clusters 1 and 2 (risk ratio, 0.37; 95% confidence interval, 0.17-0.83; p = 0.026 and risk ratio, 0.42; 95% confidence interval, 0.20-0.89; P = 0.019, respectively). There was no difference in the proportion of relapsed patients between clusters 1 and 2. CONCLUSIONS: Our cluster analysis shows that anti-SS-A/Ro52 or any anti-ARS antibodies or both might be relevant to clinical outcomes.

DOI： 10.1097/RHU.0000000000000836

Regulation of Cathepsin E gene expression by the transcription factor Kaiso in MRL/lpr mice derived CD4+ T cells. Reviewed International journal

Sumie Hiramatsu, Katsue S Watanabe, Sonia Zeggar, Yosuke Asano, Yoshia Miyawaki, Yuriko Yamamura, Eri Katsuyama, Takayuki Katsuyama, Haruki Watanabe, Mariko Takano-Narazaki, Yoshinori Matsumoto, Tomoko Kawabata, Ken-Ei Sada, Jun Wada

Scientific reports 9 ( 1 ) 3054 - 3054 2019.2

Language：English Publishing type：Research paper (scientific journal)

Global DNA hypomethylation in CD4+ cells in systemic lupus erythematosus (SLE) was suggested to play a key role in the pathogenesis. To identify new methylation-sensitive genes, we integrated genome-wide DNA methylation and mRNA profiling data in CD4+ cells of MRL/lpr (MRL) and C57BL6/J (B6) mice. We identified Cathepsin E (Ctse), in which 13 methyl-CpGs within 583 bp region of intron 1 were hypomethylated, and Ctse mRNA upregulated in MRL compared with B6 mice. One of methyl-CpGs, mCGCG was 93.3 ± 2.05% methylated in B6 mice, while 80.0 ± 6.2% methylated and mutated to CGGG in MRL mice. Kaiso is known to bind to mCGCG and we hypothesized that it represses expression of Ctse in B6 mice. The binding of Kaiso to mCGCG site in B6 mice was reduced in MRL mice revealed by ChIP-PCR. EL4 cells treated with 5-azaC and/or Trichostatin A showed the suppression of binding of Kaiso to mCGCG motif by ChIP-PCR and the overexpression of Ctse was demonstrated by qPCR. Ctse gene silencing by siRNA in EL4 cells resulted in reduction of IL-10 secretion. The hypomethylation of mCGCG motif, reduced recruitment of Kaiso, and increased expression of Ctse and Il-10 in CD4+ cells may be involved in the pathogenesis of SLE.

DOI： 10.1038/s41598-019-38809-y

Decreased Expression of Serine/Arginine-Rich Splicing Factor 1 in T Cells From Patients With Active Systemic Lupus Erythematosus Accounts for Reduced Expression of RasGRP1 and DNA Methyltransferase 1. Reviewed International journal

Michihiro Kono, Takashi Kurita, Shinsuke Yasuda, Michihito Kono, Yuichiro Fujieda, Toshiyuki Bohgaki, Takayuki Katsuyama, George C Tsokos, Vaishali R Moulton, Tatsuya Atsumi

Arthritis & rheumatology (Hoboken, N.J.) 70 ( 12 ) 2046 - 2056 2018.12

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: T cells from systemic lupus erythematosus (SLE) patients have reduced protein levels of RasGRP1, a guanine nucleotide exchange factor for Ras, and increased transcript of alternatively spliced (AS) forms lacking exon 11. Serine/arginine-rich splicing factor 1 (SRSF1) binds pre-messenger RNA (pre-mRNA) to regulate AS forms of several genes, including CD3ζ in SLE T cells. This study was undertaken to assess whether SRSF1 controls the expression of RasGRP1 in T cells from patients with SLE. METHODS: We studied T cells from 45 SLE patients and 18 healthy subjects. Expression levels of SRSF1, wild-type (WT) RasGRP1, and DNA methyltransferase 1 (DNMT1) were assessed by quantitative polymerase chain reaction. Direct binding of SRSF1 to exon 11 of RasGRP1 mRNA was evaluated with an oligonucleotide-protein pulldown assay. Healthy T cells and SLE T cells were treated with SRSF1-specific small interfering RNA or SRSF1 expression vector, respectively, and then evaluated for mRNA/protein expression. RESULTS: SRSF1 expression levels were significantly lower in T cells from SLE patients compared to those from healthy subjects, and correlated inversely with disease activity and positively with levels of RasGRP1-WT and DNMT1. SRSF1 bound directly to exon 11 of RasGRP1 mRNA. Silencing of SRSF1 in human T cells led to increased ratios of RasGRP1-AS to RasGRP1-WT and decreased levels of RasGRP1 protein, whereas overexpression of SRSF1 in SLE T cells caused recovery of RasGRP1, which in turn induced DNMT1/interleukin-2 expression. CONCLUSION: SRSF1 controls the alternative splicing of RasGRP1 and subsequent protein expression. Our findings extend evidence that alternative splicing plays a central role in the aberrant T cell function in patients with SLE by controlling the expression of multiple genes.

DOI： 10.1002/art.40585

Correction: Downregulation of miR-200a-3p, Targeting CtBP2 Complex, Is Involved in the Hypoproduction of IL-2 in Systemic Lupus Erythematosus-Derived T Cells. International journal

Eri Katsuyama, Minglu Yan, Katsue Sunahori Watanabe, Mariko Narazaki, Syun Matsushima, Yuriko Yamamura, Sumie Hiramatsu, Keiji Ohashi, Haruki Watanabe, Takayuki Katsuyama, Sonia Zeggar, Nobuya Yoshida, Vaishali R Moulton, George C Tsokos, Ken-Ei Sada, Jun Wada

Journal of immunology (Baltimore, Md. : 1950) 201 ( 3 ) 1104 - 1104 2018.8

広範囲な全身動脈炎を来したIgG4関連疾患の症例

山村裕理子, 内田成彦, 川畑智子, 林啓悟, 平松澄恵, 森下美智子, 宮脇義亜, 大橋敬司, 勝山恵理, 勝山隆行, 渡辺晴樹, 楢崎真理子, 建部智子, 渡部克枝, 佐田憲映, 和田淳

岡山医学会雑誌 130 ( 2 ) 98 - 98 2018.8

Role of Lgals9 Deficiency in Attenuating Nephritis and Arthritis in BALB/c Mice in a Pristane-Induced Lupus Model. Reviewed International journal

Sonia Zeggar, Katsue S Watanabe, Sanae Teshigawara, Sumie Hiramatsu, Takayuki Katsuyama, Eri Katsuyama, Haruki Watanabe, Yoshinori Matsumoto, Tomoko Kawabata, Ken-Ei Sada, Toshiro Niki, Mitsuomi Hirashima, Jun Wada

Arthritis & rheumatology (Hoboken, N.J.) 70 ( 7 ) 1089 - 1101 2018.7

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: In systemic lupus erythematosus (SLE), an autoimmune disease associated with multiple organ involvement, the development of lupus nephritis determines prognosis, and arthritis impairs quality of life. Galectin 9 (Gal-9, Lgals9) is a β-galactoside-binding lectin that has been used for clinical application in autoimmune diseases, since recombinant Gal-9, as a ligand for T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), induces apoptosis of activated CD4+TIM-3+ Th1 cells. This study was undertaken to investigate whether deficiency of Lgals9 has beneficial or deleterious effects on lupus in a murine model. METHODS: Gal-9+/+ and Gal-9-/- female BALB/c mice were injected with pristane, and the severity of arthritis, proteinuria, and levels of autoantibody production were assessed at several time points immediately following injection. At 7 months after pristane injection, renal pathologic features, the severity of joint inflammation, and formation of lipogranulomas were evaluated. Subsets of inflammatory cells in the spleen and peritoneal lavage were characterized, and expression levels of cytokines from peritoneal macrophages were analyzed. RESULTS: Lgals9 deficiency protected against the development of immune complex glomerulonephritis, arthritis, and peritoneal lipogranuloma formation in BALB/c mice in this murine model of pristane-induced lupus. The populations of T cell subsets and B cells in the spleen and peritoneum were not altered by Lgals9 deficiency in pristane-injected BALB/c mice. Furthermore, Lgals9 deficiency protected against pristane-induced lupus without altering the Toll-like receptor 7-type I interferon pathway. CONCLUSION: Gal-9 is required for the induction and development of lupus nephritis and arthritis in this murine model of SLE. The results of the current investigation provide a potential new strategy in which antagonism of Gal-9 may be beneficial for the treatment of nephritis and arthritis in patients with SLE through targeting of activated macrophages.

DOI： 10.1002/art.40467

Downregulation of CD3ζ in NK Cells from Systemic Lupus Erythematosus Patients Confers a Proinflammatory Phenotype. Reviewed International journal

Abel Suárez-Fueyo, Sean J Bradley, Takayuki Katsuyama, Sarah Solomon, Eri Katsuyama, Vasileios C Kyttaris, Vaishali R Moulton, George C Tsokos

Journal of immunology (Baltimore, Md. : 1950) 200 ( 9 ) 3077 - 3086 2018.5

Language：English Publishing type：Research paper (scientific journal)

Cytotoxic function and cytokine profile of NK cells are compromised in patients with systemic lupus erythematosus (SLE). CD3ζ, an important molecule for NK cell activation, is downregulated in SLE T cells and contributes to their altered function. However, little is known about the role of CD3ζ in SLE NK cells. We studied CD3ζ levels and its contribution to cytotoxic, degranulation, and cytokine production capacity of NK cells from patients with SLE. Furthermore, we studied the human NK cell line, NKL, in which manipulation of CD3ζ levels was achieved using small interfering RNA and NK cells from Rag2 mice deficient in CD3ζ. We found reduced CD3ζ expression in NK cells from SLE patients independent of disease activity. Downregulation of CD3ζ expression in NK cells is mediated, at least in part, by Caspase 3, the activity of which is higher in NK cells from patients with SLE compared with NK cells from healthy donors. CD3ζ levels correlated inversely with natural cytotoxicity and the percentage of cells capable of producing the proinflammatory cytokines IFN-γ and TNF. In contrast, CD3ζ levels showed a direct correlation with levels of Ab-dependent cellular cytotoxicity. Experiments performed in CD3ζ-silenced NKL and CD3ζ-deficient NK cells from Rag2 mice confirmed the dependence of NK cell function on CD3ζ levels. Our results demonstrate a differential role for CD3ζ in natural cytotoxicity and Ab-dependent cellular cytotoxicity. We conclude that downregulated CD3ζ confers a proinflammatory phenotype to SLE NK cells and contributes to their altered function in patients with SLE.

DOI： 10.4049/jimmunol.1700588

SLE・抗リン脂質抗体症候群1 全身性エリテマトーデスの妊娠と慢性障害に関する検討

森下美智子, 大橋敬司, 宮脇義亜, 佐田憲映, 浅野洋介, 林啓悟, 平松澄恵, 山村裕理子, 勝山恵理, 勝山隆行, 渡辺晴樹, 楢崎真理子, 建部智子, 松本佳則, 渡部克枝, 川畑智子, 矢嶋宣幸, 和田淳

日本リウマチ学会総会・学術集会プログラム・抄録集 62回 444 - 444 2018.3

Anti-SS-A/Ro antibody positivity as a risk factor for relapse in patients with polymyositis/dermatomyositis. Reviewed International journal

Noriko Tatebe, Ken-Ei Sada, Yosuke Asano, Sonia Zeggar, Sumie Hiramatsu, Yoshia Miyawaki, Keiji Ohashi, Michiko Morishita, Takayuki Katsuyama, Eri Katsuyama, Haruki Watanabe, Mariko Narazaki, Katsue Watanabe, Tomoko Kawabata, Jun Wada

Modern rheumatology 28 ( 1 ) 141 - 146 2018.1

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: The objective of this study is to elucidate predictors of relapse in patients with polymyositis and dermatomyositis (PM/DM). METHODS: Fifty PM/DM patients who achieved disease stabilization at Okayama University Hospital in 2004-2014 were enrolled retrospectively. Candidate predictors such as demographic factors, clinical symptoms, laboratory data, and treatment status were compared. RESULTS: The mean age of enrolled patients was 58 years; 34 were female. The patient groupings were as follows: 21 with PM, 27 with DM, and two with clinically amyopathic DM. During a mean observation period of 685 d, 5 patients (10%) died and 20 (40%) relapsed. The relapsed patients displayed baseline muscle weakness less frequently (85% versus 100%, p = .03) and anti-SS-A/Ro antibody more frequently (65% versus 27%, p = .007). Anti-SS-A/Ro-positive patients exhibited a higher relapse rate than anti-SS-A/Ro-negative patients (log-rank test, p = .03). Anti-SS-A/Ro-positive patients also exhibited higher anti-Jo-1 antibody positivity and lower levels of serum complement. After adjusting anti-Jo-1 antibody positivity, age, sex, CK <500 IU/L, and lung involvement, anti-SS-A/Ro positivity was still an independent risk factor for higher relapse-rate (odds ratio, 5.5; 95% confidence interval, 1.4-25.1). CONCLUSIONS: Anti-SS-A/Ro antibody positivity may be a useful biomarker for prediction of relapse.

DOI： 10.1080/14397595.2017.1317377

Aberrant T Cell Signaling and Subsets in Systemic Lupus Erythematosus. Invited Reviewed International journal

Takayuki Katsuyama, George C Tsokos, Vaishali R Moulton

Frontiers in immunology 9 1088 - 1088 2018

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

Systemic lupus erythematosus (SLE) is a chronic multi-organ debilitating autoimmune disease, which mainly afflicts women in the reproductive years. A complex interaction of genetics, environmental factors and hormones result in the breakdown of immune tolerance to "self" leading to damage and destruction of multiple organs, such as the skin, joints, kidneys, heart and brain. Both innate and adaptive immune systems are critically involved in the misguided immune response against self-antigens. Dendritic cells, neutrophils, and innate lymphoid cells are important in initiating antigen presentation and propagating inflammation at lymphoid and peripheral tissue sites. Autoantibodies produced by B lymphocytes and immune complex deposition in vital organs contribute to tissue damage. T lymphocytes are increasingly being recognized as key contributors to disease pathogenesis. CD4 T follicular helper cells enable autoantibody production, inflammatory Th17 subsets promote inflammation, while defects in regulatory T cells lead to unchecked immune responses. A better understanding of the molecular defects including signaling events and gene regulation underlying the dysfunctional T cells in SLE is necessary to pave the path for better management, therapy, and perhaps prevention of this complex disease. In this review, we focus on the aberrations in T cell signaling in SLE and highlight therapeutic advances in this field.

DOI： 10.3389/fimmu.2018.01088

Central Diabetes Insipidus in Refractory Antineutrophil Cytoplasmic Antibody-associated Vasculitis. Reviewed

Keiji Ohashi, Michiko Morishita, Haruki Watanabe, Ken-Ei Sada, Takayuki Katsuyama, Yoshia Miyawaki, Eri Katsuyama, Mariko Narazaki, Noriko Tatebe, Katsue Watanabe, Tomoko Kawabata, Jun Wada

Internal medicine (Tokyo, Japan) 56 ( 21 ) 2943 - 2948 2017.11

Language：English Publishing type：Research paper (scientific journal)

We herein describe two cases of refractory antineutrophil cytoplasmic antibody-associated vasculitis (AAV) complicated with diabetes insipidus (DI) possibly related to hypertrophic pachymeningitis (HP). One patient had microscopic polyangiitis and HP, which were refractory to cyclophosphamide, azathioprine, rituximab, mycophenolate mofetil (MMF), and mizoribine. Remission was finally achieved with the use of etanercept, but DI occurred 5 years later. The other patient had granulomatosis with polyangiitis, which that was refractory to cyclophosphamide, methotrexate, MMF, and rituximab. DI subsequently developed, but was successfully treated with etanercept. Dura mater hypertrophy was macroscopically observed in the latter case.

DOI： 10.2169/internalmedicine.8683-16

Alternative to Rituximab Therapy for a Patient with Ankylosing Spondylitis Who Was Unable to Continue Anti-TNF Therapy. Reviewed

Eri Katsuyama, Hiroshi Wakabayashi, Ken-Ei Sada, Sumie Hiramatsu, Yoshia Miyawaki, Michiko Morishita, Keiji Ohashi, Haruki Watanabe, Takayuki Katsuyama, Sonia Zeggar, Mariko Narazaki, Noriko Tatebe, Katsue Sunahori-Watanabe, Tomoko Kawabata, Jun Wada

Acta medica Okayama 71 ( 5 ) 445 - 448 2017.10

Language：English Publishing type：Research paper (scientific journal)

We herein present a case of a 38-year-old man who had bamboo spine and severe sacroiliitis and who was diagnosed with ankylosing spondylitis (AS). Infliximab (IFX) markedly improved the axial symptom but was discontinued due to the side effect of peripheral neuropathy. Switching from IFX to etanercept worsened the side effect. Rituximab (RTX) administration elicited a good response without side effects. RTX might be a suitable option for AS therapy when TNF inhibitors are difficult to use.

DOI： 10.18926/AMO/55444

Prognostic factors of methotrexate-associated lymphoproliferative disorders associated with rheumatoid arthritis and plausible application of biological agents. Reviewed International journal

Takayuki Katsuyama, Ken-Ei Sada, Minglu Yan, Sonia Zeggar, Sumie Hiramatsu, Yoshia Miyawaki, Keiji Ohashi, Michiko Morishita, Haruki Watanabe, Eri Katsuyama, Mariko Takano-Narazaki, Noriko Toyota-Tatebe, Katsue Sunahori-Watanabe, Tomoko Kawabata, Kohei Miyake, Toru Kiguchi, Jun Wada

Modern rheumatology 27 ( 5 ) 773 - 777 2017.9

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: To determine prognostic factors of methotrexate-associated lymphoproliferative disorder (MTX-LPD) and evaluate the efficacy and safety of biological therapy in rheumatoid arthritis (RA) complicated with MTX-LPD. METHODS: Thirty RA patients who developed MTX-LPD were investigated in this study. We compared the clinical and laboratory parameters of patients who achieved regression of LPD by MTX withdrawal with those who required chemotherapy and evaluated the clinical course of RA after LPD development. RESULTS: Twenty-three patients (76.7%) achieved regression of LPD by MTX withdrawal. Chemotherapy-free patients had a tendency of shorter RA duration (13.1 vs. 22.0 years, p = 0.108) and higher doses of MTX at LPD diagnosis (8.0 vs. 5.3 mg/w, p = 0.067) than patients who required chemotherapy. A significantly higher positive rate of peripheral blood Epstein-Barr virus (EBV)-DNA was observed in the chemotherapy-free group (9/9 vs. 0/3, p = 0.0002). Of 15 patients that received biological agents after LPD development, 14 patients (93.3%) demonstrated an improved disease activity of RA and persistent remission of LPD, whereas only one patient experienced relapse of LPD during tocilizumab therapy. CONCLUSIONS: Peripheral blood EBV-DNA positivity is a potential prognostic marker of better outcome in MTX-LPD. Biological agents could be an option for the treatment of RA patients with MTX-LPD.

DOI： 10.1080/14397595.2016.1259714

Downregulation of miR-200a-3p, Targeting CtBP2 Complex, Is Involved in the Hypoproduction of IL-2 in Systemic Lupus Erythematosus-Derived T Cells. Reviewed International journal

Eri Katsuyama, Minglu Yan, Katsue Sunahori Watanabe, Mariko Narazaki, Syun Matsushima, Yuriko Yamamura, Sumie Hiramatsu, Keiji Ohashi, Haruki Watanabe, Takayuki Katsuyama, Sonia Zeggar, Nobuya Yoshida, Vaishali R Moulton, George C Tsokos, Ken-Ei Sada, Jun Wada

Journal of immunology (Baltimore, Md. : 1950) 198 ( 11 ) 4268 - 4276 2017.6

Language：English Publishing type：Research paper (scientific journal)

Systemic lupus erythematosus (SLE) damages multiple organs by producing various autoantibodies. In this study, we report that decreased microRNA (miR)-200a-3p causes IL-2 hypoproduction through zinc finger E-box binding homeobox (ZEB)1 and C-terminal binding protein 2 (CtBP2) in a lupus-prone mouse. First, we performed RNA sequencing to identify candidate microRNAs and mRNAs involved in the pathogenesis of SLE. We found that miR-200a-3p was significantly downregulated, whereas its putative targets, ZEB2 and CtBP2, were upregulated in CD4+ T cells from MRL/lpr-Tnfrsf6lpr mice compared with C57BL/6J mice. ZEB1 and ZEB2 comprise the ZEB family and suppress various genes, including IL-2 by recruiting CtBP2. IL-2 plays a critical role in immune tolerance, and insufficient IL-2 production upon stimulation has been recognized in SLE pathogenesis. Therefore, we hypothesized that decreased miR-200a-3p causes IL-2 deficit through the ZEB1-CtBP2 and/or ZEB2-CtBP2 complex in SLE CD4+ T cells. Overexpression of miR-200a-3p induced IL-2 production by downregulating ZEB1, ZEB2, and CtBP2 in EL4 cell lines. We further revealed that miR-200a-3p promotes IL-2 expression by reducing the binding of suppressive ZEB1-CtBP2 and ZEB2-CtBP2 complexes on negative regulatory element A in the IL-2 promoter in EL4 cells. Interestingly, the ZEB1-CtBP2 complex on negative regulatory element A was significantly upregulated after PMA/ionomycin stimulation in lupus CD4+ T cells. Our studies have revealed a new epigenetic pathway in the control of IL-2 production in SLE whereby low levels of miR-200a-3p accumulate the binding of the ZEB1-CtBP2 complex to the IL-2 promoter and suppress IL-2 production.

DOI： 10.4049/jimmunol.1601705

間質性肺炎急性増悪にて死亡したシェーグレン症候群合併顕微鏡的多発血管炎の一例

大橋敬司, 宮脇義亜, 佐田憲映, 平松澄恵, 森下美智子, 勝山恵理, 勝山隆行, 渡辺晴樹, 楢崎真理子, 建部智子, 渡部克枝, 川畑智子, 和田淳

岡山医学会雑誌 129 ( 1 ) 67 - 67 2017.4

IgA腎症に対する扁摘パルス療法時のステロイド糖尿病発症と短期アウトカムの検討

宮脇義亜, 佐田憲映, 勝山隆行, 渡辺晴樹, 井上達之, 木野村賢, 杉山斉, 和田淳

日本腎臓学会誌 59 ( 3 ) 299 - 299 2017.4

Combined Effects of Androgen and Growth Hormone on Osteoblast Marker Expression in Mouse C2C12 and MC3T3-E1 Cells Induced by Bone Morphogenetic Protein. Reviewed International journal

Kosuke Kimura, Tomohiro Terasaka, Nahoko Iwata, Takayuki Katsuyama, Motoshi Komatsubara, Ryota Nagao, Kenichi Inagaki, Fumio Otsuka

Journal of clinical medicine 6 ( 1 ) 2017.1

Language：English Publishing type：Research paper (scientific journal)

Osteoblasts undergo differentiation in response to various factors, including growth factors and steroids. Bone mass is diminished in androgen- and/or growth hormone (GH)-deficient patients. However the functional relationship between androgen and GH, and their combined effects on bone metabolism, remains unclear. Here we investigated the mutual effects of androgen and GH on osteoblastic marker expression using mouse myoblastic C2C12 and osteoblast-like MC3T3-E1 cells. Combined treatment with dihydrotestosterone (DHT) and GH enhanced BMP-2-induced expression of Runx2, ALP, and osteocalcin mRNA, compared with the individual treatments in C2C12 cells. Co-treatment with DHT and GH activated Smad1/5/8 phosphorylation, Id-1 transcription, and ALP activity induced by BMP-2 in C2C12 cells but not in MC3T3-E1 cells. The insulin-like growth factor (IGF-I) mRNA level was amplified by GH and BMP-2 treatment and was restored by co-treatment with DHT in C2C12 cells. The mRNA level of the IGF-I receptor was not significantly altered by GH or DHT, while it was increased by IGF-I. In addition, IGF-I treatment increased collagen-1 mRNA expression, whereas blockage of endogenous IGF-I activity using an anti-IGF-I antibody failed to suppress the effect of GH and DHT on BMP-2-induced Runx2 expression in C2C12 cells, suggesting that endogenous IGF-I was not substantially involved in the underlying GH actions. On the other hand, androgen receptor and GH receptor mRNA expression was suppressed by BMP-2 in both cell lines, implying the existence of a feedback action. Collectively the results showed that the combined effects of androgen and GH facilitated BMP-2-induced osteoblast differentiation at an early stage by upregulating BMP receptor signaling.

DOI： 10.3390/jcm6010006

A retrospective observational study of glucocorticoid-induced diabetes mellitus with IgA nephropathy treated with tonsillectomy plus methylprednisolone pulse therapy. Reviewed International journal

Yoshia Miyawaki, Takayuki Katsuyama, Ken-Ei Sada, Sumie Hiramatsu, Keiji Ohashi, Michiko Morishita, Eri Katsuyama, Haruki Watanabe, Mariko Takano-Narazaki, Noriko Toyota-Tatebe, Katsue Sunahori-Watanabe, Tomoko Kawabata, Tatsuyuki Inoue, Masaru Kinomura, Hitoshi Sugiyama, Jun Wada

PloS one 12 ( 5 ) e0178018 2017

Language：English Publishing type：Research paper (scientific journal)

AIMS: To evaluate the incidence of GC-DM among patients with immunoglobulin A nephropathy (IgAN) and to confirm the risk factors for the development of GC-DM. METHODS: The medical records of patients with IgAN newly treated with the protocol of tonsillectomy combined with steroid pulse therapy were reviewed. The primary outcome was the development of GC-DM within the hospitalization period and during one year of follow-up. RESULTS: During hospitalization, 19 of the 95 patients developed GC-DM (20.0%), and the patients with GC-DM were significantly older and had a higher rate of family history of diabetes and higher HbA1c levels. The prevalence of hypertension was higher and the eGFR was numerically lower in patients with GC-DM than in those without. Older age (≥45 years) and a family history of diabetes emerged as independent risk factors for the development of GC-DM (odds ratio [OR], 6.3 and 95% confidence interval [CI], 1.6-27.6; OR, 4.4 and 95% CI, 1.2-16.6, respectively). No patients were newly diagnosed with GC-DM during 1-year observation period at out-patient clinic. CONCLUSIONS: Among the patients with IgAN, 20% developed GC-DM during the hospitalization period, confirming the family history of diabetes is clinically necessary before starting GC therapy.

DOI： 10.1371/journal.pone.0178018

Azathioprine Intolerance in Japanese Patients with Antineutrophil Cytoplasmic Antibody-associated Vasculitis. Reviewed

Michiko Morishita, Haruki Watanabe, Minglu Yan, Sonia Zeggar, Sumie Hiramatsu, Keiji Ohashi, Yoshia Miyawaki, Eri Katsuyama, Takayuki Katsuyama, Mariko Takano Narazaki, Noriko Toyota Tatebe, Katsue Sunahori Watanabe, Tomoko Kawabata, Ken-Ei Sada, Jun Wada

Internal medicine (Tokyo, Japan) 56 ( 13 ) 1645 - 1650 2017

Language：English Publishing type：Research paper (scientific journal)

Objective To assess the safety of azathioprine (AZA) in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Methods We retrospectively enrolled 67 consecutive AAV patients who had initiated AZA treatment from January 2006 to August 2014 at Okayama University Hospital. We evaluated the development of severe adverse events (AEs), AZA discontinuation due to total AEs (severe AEs included) within 1 year, and AZA-associated risk factors. Results The patients' median age was 70 years old. Forty-nine women and 18 men participated at the initiation of the study. Fifty-eight (87%) patients experienced AEs, and 36 experienced severe AEs (21 hepatic and 11 cytopenic severe AEs). Thirty-one (46%) patients discontinued treatment because of AEs. Abnormal hepatic laboratory test results at the treatment initiation were more frequent in patients with hepatic severe AEs and were associated with treatment discontinuation. The leukocyte and neutrophil counts at the treatment initiation were lower in the patients who discontinued treatment because of cytopenic AEs than in those who continued treatment. Only two patients experienced flare-ups during treatment. Conclusion The AE-associated AZA discontinuation rate in Japanese AAV patients was relatively high. AZA use warrants caution in patients with abnormal hepatic laboratory test results or low leukocyte or neutrophil counts.

DOI： 10.2169/internalmedicine.56.8287

Development of intracerebral hemorrhage in the short-term clinical course of a patient with microscopic polyangiitis without neurological symptoms at diagnosis: an autopsy case. Reviewed

Yoshia Miyawaki, Takayuki Katsuyama, Ken-Ei Sada, Kohei Taniguchi, Yuki Kakio, Jun Wada

CEN case reports 5 ( 2 ) 173 - 178 2016.11

Language：English Publishing type：Research paper (scientific journal)

A 77-year-old man with high-grade fever, progressive renal dysfunction, high serum level of C-reactive protein and positive serum myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) was diagnosed with microscopic polyangiitis with rapidly progressive glomerulonephritis, and remission induction treatment with glucocorticoids and intravenous cyclophosphamide was initiated. Although his general condition improved in a short time, intracerebral hemorrhage occurred 12 days after the initiation of treatment and emergent hematoma evacuation was performed. However, he passed away on day 14. Surprisingly, even though no clinical findings for any organs except for renal involvement was detected before his death, autopsy revealed necrotizing vasculitis affecting various systemic organs including kidney, pancreas, liver, myocardium in ventricle, adipose tissue of the left adrenal gland, small intestine, gallbladder, bronchus, prostate, testis and spleen. It is difficult to detect widespread vasculitis without clinical symptoms and signs in patients with ANCA-associated vasculitis. A whole body assessment tool is necessary to detect unexpected vital organ damage, including cerebral vessels.

DOI： 10.1007/s13730-016-0219-0

多発性筋炎・皮膚筋炎抗SS-A抗体は多発性筋炎/皮膚筋炎における再燃危険因子である Reviewed

建部智子, 佐田憲映, 浅野洋介, 平松澄恵, 宮脇義亜, 森下美智子, 大橋敬司, 渡辺晴樹, 勝山隆行, 勝山恵理, 楢崎真理子, 渡部克枝, 杉山晃一, 若林宏, 川畑智子, 和田淳

日本リウマチ学会総会・学術集会プログラム・抄録集 60回 453 - 453 2016.3

脊椎関節炎、その他リナグリプチンの予防内服によるステロイド糖尿病の発症抑制効果に関するパイロット研究

宮脇義亜, 佐田憲映, 平松澄恵, 大橋敬司, 森下美智子, 勝山隆行, 勝山恵理, 渡辺晴樹, 楢崎真理子, 建部智子, 渡部克枝, 川畑智子, 和田淳

日本リウマチ学会総会・学術集会プログラム・抄録集 60回 401 - 401 2016.3

The efficacy of add-on tacrolimus for minor flare in patients with systemic lupus erythematosus: a retrospective study

H. Watanabe, R. Yamanaka, KE Sada, S. Zeggar, E. Katsuyama, T. Katsuyama, M. T. Narazaki, N. T. Tatebe, K. Sugiyama, K. S. Watanabe, H. Wakabayashi, T. Kawabata, J. Wada, H. Makino

LUPUS 25 ( 1 ) 54 - 60 2016.1

Language：English Publishing type：Research paper (scientific journal) Publisher：SAGE PUBLICATIONS LTD

Objective We have assessed the effectiveness of tacrolimus for minor flares in systemic lupus erythematosus (SLE) patients.
Methods The medical records of 313 patients were retrospectively reviewed over a period of seven years, from 2006 to 2013. We enrolled patients with minor flare treated with add-on tacrolimus, without glucocorticoid (GC) intensification (tacrolimus group). Minor flare was defined as a 1-point increase in a total score between 3 and 11 in the SLE Disease Activity Index (SLEDAI). We enrolled as controls patients who were administered increased doses of GC for minor flare (GC group). All patients were followed for one year. The primary outcome measure was the proportion of responders.
Results There were 14 eligible patients in the tacrolimus group and 20 eligible patients in the GC group. The mean SLEDAI at flare tended to be higher in the tacrolimus group than in the GC group (7.5 vs. 6.2, p=0.085). A mean dose of 1.6mg tacrolimus/day was administered for flare, while the mean GC dose was 13.7mg/day in the GC group. The proportion of responders was 86% (12/14) in the tacrolimus group and 75% (15/20) in the GC group (p=0.67). The mean dose of GC at 12 months was higher in the GC group than in the tacrolimus group (9.7mg/day vs. 7.1mg/day, p<0.05). Only one patient discontinued tacrolimus because of fatigue after three months.
Conclusion Adding tacrolimus without increasing the GC dose may provide an effective treatment option for minor flares in patients with SLE.

DOI： 10.1177/0961203315600538

Bilateral Abducens Nerve Palsy due to Idiopathic Intracranial Hypertension as an Initial Manifestation of Systemic Lupus Erythematosus. Reviewed

Eri Katsuyama, Ken-Ei Sada, Noriko Tatebe, Haruki Watanabe, Takayuki Katsuyama, Mariko Narazaki, Koichi Sugiyama, Katsue S Watanabe, Hiroshi Wakabayashi, Tomoko Kawabata, Jun Wada, Hirofumi Makino

Internal medicine (Tokyo, Japan) 55 ( 8 ) 991 - 4 2016

Language：English Publishing type：Research paper (scientific journal)

Idiopathic intracranial hypertension (IIH) is a syndrome of increased intracranial pressure and presents as an intractable headache, vomiting, and ophthalmologic manifestations. We herein report the case of a young girl who presented with bilateral abducens nerve palsy due to IIH as the onset of systemic lupus erythematosus (SLE). The patient was successfully treated with corticosteroid therapy. Our case lacked the typical symptoms of IIH, such as headache or nausea; therefore, it is necessary to carefully determine the cause of bilateral abducens nerve palsies. The development of IIH in SLE patients is a rare occurrence, but this manifestation should not be overlooked.

DOI： 10.2169/internalmedicine.55.5990

Regulatory effects of fibroblast growth factor-8 and tumor necrosis factor-α on osteoblast marker expression induced by bone morphogenetic protein-2. Reviewed International journal

Takayuki Katsuyama, Fumio Otsuka, Tomohiro Terasaka, Kenichi Inagaki, Mariko Takano-Narazaki, Yoshinori Matsumoto, Ken-Ei Sada, Hirofumi Makino

Peptides 73 88 - 94 2015.11

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

BMP induces osteoblast differentiation, whereas a key proinflammatory cytokine, TNF-α, causes inflammatory bone damage shown in rheumatoid arthritis. FGF molecules are known to be involved in bone homeostasis. However, the effects of FGF-8 on osteoblast differentiation and the interaction between FGF-8, BMPs and TNF-α have yet to be clarified. Here we investigated the effects of FGF-8 in relation to TNF-α actions on BMP-2-induced osteoblast marker expression using myoblast cell line C2C12, osteoblast precursor cell line MC3T3-E1 and rat calvarial osteoblasts. It was revealed that FGF-8 inhibited BMP-2-induced expression of osteoblast differentiation markers, including Runx2, osteocalcin, alkaline phosphatase, type-1 collagen and osterix, in a concentration-dependent manner. The inhibitory effects of FGF-8 on BMP-induced osteoblast differentiation and Smad1/5/8 activation were enhanced in the presence of TNF-α action. FGF-8 also inhibited BMP-2-induced expression of Wnt5a, which activates a non-canonical Wnt signaling pathway. FGF-8 had no significant influence on the expression levels of TNF receptors, while FGF-8 suppressed the expression of inhibitory Smad6 and Smad7, suggesting a possible feedback activity through FGF to BMP receptor (BMPR) signaling. Of note, inhibition of ERK activity and FGF receptor (FGFR)-dependent protein kinase, but not JNK or NFκB pathway, suppressed the FGF-8 actions on BMP-induced osteoblast differentiation. FGF-8 was revealed to suppress BMP-induced osteoblast differentiation through the ERK pathway and the effects were enhanced by TNF-α. Given the finding that FGF-8 expression was increased in synovial tissues of rheumatoid arthritis, the functional interaction between FGFR and BMPR signaling may be involved in the development process of inflammatory bone damage.

DOI： 10.1016/j.peptides.2015.09.007

Risk factors for the development of glucocorticoid-induced diabetes mellitus. Reviewed International journal

Takayuki Katsuyama, Ken-Ei Sada, Sayaka Namba, Haruki Watanabe, Eri Katsuyama, Toshio Yamanari, Jun Wada, Hirofumi Makino

Diabetes research and clinical practice 108 ( 2 ) 273 - 9 2015.5

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

AIMS: To evaluate the incidence of glucocorticoid-induced diabetes mellitus (GC-DM) by repeated measurements of the postprandial glucose and detect predictors for the development of GC-DM. METHODS: Inpatients with rheumatic or renal disease who received glucocorticoid therapy were enrolled in this study. We compared the clinical and laboratory parameters of the GC-DM group with the non-GC-DM group and performed a multivariate analysis to identify risk factors. RESULTS: During a four-week period, 84 of the 128 patients (65.6%) developed GC-DM. All patients were diagnosed based on the detection of postprandial hyperglycemia. The GC-DM group had an older age (65.2 vs. 50.4 years, p<0.0001), higher levels of fasting plasma glucose (93.3 vs. 89.0mg/dl, p=0.027) and HbA1c (5.78 vs. 5.50%, 39.7 vs. 36.6 mmol/mol, p=0.001) and lower eGFR values (54.0 vs. 77.1 ml/min/1.73 m(2), p=0.0003) than the non-GC-DM group. According to the multivariate analysis, an older age (more than or equal to 65 years), higher HbA1c level (more than or equal to 6.0%) and lower eGFR (<40 ml/min/1.73m(2)) were identified as independent risk factors for GC-DM (OR 2.95, 95% CI 1.15-7.92, OR: 3.05, 95% CI 1.11-9.21, OR: 3.42, 95% CI: 1.22-10.8, respectively). The risk ratio for the development of GC-DM in the patients with at least one of these three risk factors was 2.28. The dose of glucocorticoids was not statistically related to the development of GC-DM. CONCLUSIONS: Patients with an older age, higher HbA1c level and lower eGFR require close monitoring for the development of GC-DM, regardless of the dose of glucocorticoids being administered.

DOI： 10.1016/j.diabres.2015.02.010

顕微鏡的多発血管炎による脳出血で死亡に至った1剖検例

宮脇義亜, 佐田憲映, 大橋敬司, 森下美智子, 勝山隆行, 勝山恵理, 渡辺晴樹, 楢崎真理子, 建部智子, 杉山晃一, 渡部克枝, 若林宏, 川畑智子, 和田淳, 槇野博史

日本リウマチ学会総会・学術集会プログラム・抄録集 59回 587 - 587 2015.3

Current concept and epidemiology of systemic vasculitides. Invited Reviewed International journal

Takayuki Katsuyama, Ken-Ei Sada, Hirofumi Makino

Allergology international : official journal of the Japanese Society of Allergology 63 ( 4 ) 505 - 13 2014.12

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

Although a new classification algorithm for systemic vasculitides was proposed by Watts et al. and the Chapel Hill Consensus Conference (CHCC) was updated in 2012, there are currently no validated diagnostic criteria for systemic vasculitides. The Diagnostic and Classification Criteria for Vasculitis study (DCVAS) is a global study to develop and improve the diagnostic criteria for systemic vasculitides. The epidemiology of systemic vasculitides differs widely among countries. For example, in the case of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, patients with microscopic polyangiitis (MPA) and with positivity for MPO-ANCA are predominant in Asian countries, whereas patients with granulomatosis with polyangiitis (GPA) and with positivity for PR3-ANCA are predominant in northern Europe and the United States. Interstitial lung disease (ILD) occurs more frequently in Asian patients compared with patients in Europe. The incidence and the prevalence of large-vessel vasculitis also differ significantly. Giant cell arteritis (GCA) occurs frequently in northern Europe, unlike Takayasu arteritis (TAK). The ethnic and regional differences in the incidence, prevalence and clinical characteristics of patients with vasculitis should be recognized when we diagnose and treat patients with vasculitis using criteria, and should also be considered when interpreting the results from clinical studies.

DOI： 10.2332/allergolint.14-RAI-0778

Prophylaxis for Pneumocystis pneumonia in patients with rheumatoid arthritis treated with biologics, based on risk factors found in a retrospective study. Reviewed International journal

Takayuki Katsuyama, Kazuyoshi Saito, Satoshi Kubo, Masao Nawata, Yoshiya Tanaka

Arthritis research & therapy 16 ( 1 ) R43 2014.2

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: Pneumocystis pneumonia (PCP) is one of the most prevalent opportunistic infections in patients undergoing immunosuppressive therapy. In this article, we discuss risk factors for PCP development in patients with rheumatoid arthritis (RA) during the course of biologic therapy and describe a prophylactic treatment for PCP with trimethoprim/sulfamethoxazole (TMP/SMX). We also evaluate the effectiveness and safety of the treatment. METHODS: We retrospectively analyzed 702 RA patients who received biologic therapy and compared the characteristics of patients with vs. without PCP to identify the risk factors for PCP. Accordingly, we analyzed 214 patients who received the TMP/SMX biologic agents as prophylaxis against PCP at the start of treatment to evaluate their effectiveness and safety. RESULTS: We identified the following as risk factors for PCP: age at least 65 years (hazard ratio (HR) = 4.37, 95% confidence interval (CI) = 1.04 to 18.2), coexisting pulmonary disease (HR = 8.13, 95% CI = 1.63 to 40.0), and use of glucocorticoids (HR = 11.4, 95% CI = 1.38 to 90.9). We employed a protocol whereby patients with two or three risk factors for PCP would receive prophylactic treatment. In the study with 214 patients, there were no cases of PCP, and the incidence of PCP was reduced to 0.00 per 100 person-years compared with that before the procedure (0.93 per 100 person-years). There were no severe adverse events induced by the TMP/SMX treatment. CONCLUSIONS: RA patients with two or three risk factors for PCP who are receiving biologic therapy can benefit from safe primary prophylaxis.

DOI： 10.1186/ar4472

Epiglottic aphthous ulcers.

Hideharu Hagiya, Hiroyuki Hanakawa, Takayuki Katsuyama, Fumio Otsuka

Internal medicine (Tokyo, Japan) 53 ( 15 ) 1731 - 1731 2014

[Analysis of the relationship between polymyalgia rheumatica and matrix metalloproteinase-3 levels during the first medical examination and during treatment].

Kouhei Miyake, Takayuki Katsuyama

Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology 37 ( 1 ) 48 - 54 2014

Language：Japanese Publishing type：Research paper (scientific journal)

In the present study, we assessed the relationship between polymyalgia rheumatica (PMR) and matrix metalloproteinase-3 (MMP-3) levels during the first medical examination and during treatment. We examined 22 patients with PMR in our hospital from 2010 to 2012, in whom the diagnosis was confirmed by the 2012 Provisional Classification Criteria for PMR. The MMP-3 levels were obtained from 19 patients, and the average MMP-3 level was 200.8 ng/mL; this level increased in 15 patients. During the 1 month after treatment initiation, the average dose of prednisolones (PSL) was increased from 2.75 mg/day to 11.3 mg/day, whereas the C-reactive protein level decreased from 6.92 mg/dL to 0.33 mg/dL; however, the average MMP-3 levels increased to 225.1 ng/mL during this period. When comparing the 7 patients in whom PSL withdrawal was achieved within 1 year and the patients in whom PSL withdrawal was difficult, we noted that the MMP-3 levels were higher in the patients in whom PSL withdrawal was difficult, and the MMP-3 level at 3 months after the first medical examination was significantly higher compared to the MMP-3 level during the first medical examination (p = 0.011). Although the MMP-3 level is influenced by PSL use, the MMP-3 levels may be considered to reflect the disease activity of PMR. Thus, MMP-3 levels may be a useful predictive factor for the success of PSL withdrawal in patients with PMR.

Large vessel vasculitis with myelodysplastic syndrome. Reviewed

Takayuki Katsuyama, Haruhito Adam Uchida, Kishio Toma, Yoshinobu Maeda, Daisho Hirota, Ryoko Umebayashi, Ken-Ei Sada, Hirofumi Makino

Internal medicine (Tokyo, Japan) 53 ( 1 ) 63 - 6 2014

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

A 71-year-old woman presented with a high-grade fever, neck pain, anemia and thrombocytopenia. After performing further examinations, we concluded that she had simultaneously developed large vessel vasculitis and myelodysplastic syndrome (MDS). Although glucocorticoid administration improved her clinical symptoms, the MDS transformed into acute myeloid leukemia and she died one year after receiving the diagnosis. The occurrence of immune-mediated disorders in patients with MDS is a well-known phenomenon; however, large vessel vasculitis is a rare complication of MDS. Our case suggests that the association between systemic vasculitis and MDS may result in poor outcomes.

Estrogen facilitates osteoblast differentiation by upregulating bone morphogenetic protein-4 signaling. Reviewed International journal

Yoshinori Matsumoto, Fumio Otsuka, Mariko Takano-Narazaki, Takayuki Katsuyama, Eri Nakamura, Naoko Tsukamoto, Kenichi Inagaki, Ken-Ei Sada, Hirofumi Makino

Steroids 78 ( 5 ) 513 - 20 2013.5

Language：English Publishing type：Research paper (scientific journal)

Imbalanced functions of osteoclasts and osteoblasts are involved in various types of bone damage including postmenopausal osteoporosis. In the present study, we investigated the cellular mechanism by which estrogen interacts in the process of osteoblastic differentiation regulated by BMP-4 using mouse MC3T3-E1 cells that express estrogen receptors (ER) and BMP-4. Estradiol enhanced BMP-4-induced Runx2, osterix, ALP and osteocalcin expression in MC3T3-E1 cells. BMP-4-induced mineralization shown by Alizarin red staining was also facilitated by estrogen treatment. It was revealed that estrogen upregulated BMP-4-induced Smad1/5/8 phosphorylation, BRE-Luc activity and Id-1 mRNA expression. The expression of BMPRII was increased by estrogen in MC3T3-E1 cells, and inhibition of BMPRII or ALK-2/3 signaling impaired the effect of estrogen on BMP-4 signaling. Of note, the enhanced expression of osterix, ALP and osteocalcin mRNAs induced by BMP-4 and estrogen was reversed in the presence of an ER antagonist. Given that membrane-impermeable estrogen also upregulated BMP-4-induced expression of osteoblastic markers and Id-1 mRNA, non-genomic ER activity is involved in the mechanism by which estrogen enhances BMP-4-induced osteoblast differentiation in MC3T3-E1 cells. On the other hand, the expression of ERα and endogenous BMP-4 was suppressed by BMP-4 treatment regardless of the presence of estrogen, implying the presence of a negative feedback loop for osteoblast differentiation. Thus, estrogen is functionally involved in the process of osteoblast differentiation regulated by BMP-4 through upregulating BMP sensitivity of MC3T3-E1 cells.

DOI： 10.1016/j.steroids.2013.02.011

Rapid progression of Graves' ophthalmopathy despite the administration of thiamazole. Reviewed

Takayuki Katsuyama, Masaya Takeda, Fumio Otsuka, Kishio Toma, Kenichi Inagaki, Ken-Ei Sada, Yukari Mimura, Toshio Ogura, Hirofumi Makino

Internal medicine (Tokyo, Japan) 52 ( 20 ) 2317 - 20 2013

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

A 42-year-old female with body weight loss, finger tremors and ocular discomfort was diagnosed with Graves' disease complicated with ophthalmopathy. Thiamazole therapy rapidly improved her hyperthyroidism. However, she was admitted to our hospital because her eye symptoms acutely deteriorated over a period of two weeks. She had ocular immotility, exposure keratitis, conjunctival edema, severe proptosis and visual impairment with a high titer of serum thyroid-stimulating antibody (TSAb). Methylprednisolone pulse therapy at a dose of 500 mg/day improved her eye symptoms. Although the mechanism of the progression of Graves' ophthalmopathy has not yet been elucidated, special attention should be paid to the occurrence of ophthalmopathy even after the initiation of thiamazole therapy.

Acquired haemophilia in a patient with castleman's disease: a case report Reviewed

T. Katsuyama, K. E. Sada, A. Katayama, N. Hinamoto, H. Wakabayashi, T. Kawabata, H. Makino

HAEMOPHILIA 18 ( 4 ) e360 - e362 2012.7

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