The chest CT signs for pulmonary veno-occlusive disease correlate with pulmonary haemodynamics in systemic sclerosis.
Haruka Moriya, Masaru Kato, Ryo Hisada, Keita Ninagawa, Maria Tada, Kodai Sakiyama, Mitsutaka Yasuda, Michihito Kono, Yuichiro Fujieda, Olga Amengual, Yasuka Kikuchi, Ichizo Tsujino, Takahiro Sato, Tatsuya Atsumi
Rheumatology (Oxford, England), 2023年09月15日, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: Pulmonary arterial hypertension associated with systemic sclerosis (PAH-SSc) sometimes accompanies pulmonary veno-occlusive disease (PVOD). We aimed to reveal the relation between clinical signs of PVOD and severing of pulmonary vasculopathy in SSc. METHODS: This study comprised 52 consecutive SSc patients who had pulmonary haemodynamic abnormalities (mPAP > 20 mmHg, PVR > 2 W.U. or PAWP > 15 mmHg). The chest CT scan was evaluated in all patients. Patients were divided into two groups, the 0-1 group and the 2-3 group, according to the number of chest CT signs for PVOD, including 1) mediastinal lymph node enlargement, 2) thickened interlobular septal wall, and 3) ground glass opacity. Pulmonary haemodynamics, echocardiography and MRI-based cardiac function, pulmonary function, and serum biomarkers were compared between the two groups. RESULTS: Mediastinal lymph node enlargement, thickened interlobular septal wall, and ground glass opacity were observed in 11 (21%), 32 (62%), and 11 (21%) patients, respectively. The 2-3 group (n = 15) had higher mPAP (p= 0.02) while lower DLco/VA (p= 0.02) compared with the 0-1 group (n = 37). Other parameters, including PAWP, cardiac output, left ventricular ejection fraction, left atrial diameter, forced vital capacity, brain natriuretic peptide, and Krebs von den Lunge-6 were not different between the two groups. CONCLUSION: The CT signs for PVOD had positive correlation with mPAP but negative correlation with DLco in SSc patients, indicating that PAH-SSc may reflect a spectrum of pulmonary vascular disease that ranges from the pulmonary artery to the vein.

Clinical and Hemodynamic Responses to Imatinib in Pulmonary Veno-Occlusive Disease/Pulmonary Capillary Hemangiomatosis: A Retrospective Pilot Study of Five Cases and Review of the Literature
Junichi Nakamura, Ichizo Tsujino, Hideki Shima, Toshitaka Nakaya, Ayako Sugimoto, Takahiro Sato, Taku Watanabe, Hiroshi Ohira, Masaru Suzuki, Satonori Tsuneta, Ryo Hisada, Masaru Kato, Satoshi Konno
American Journal of Cardiovascular Drugs, 23, 3, 329, 338, Springer Science and Business Media LLC, 2023年03月30日
研究論文（学術雑誌）

Itaconate ameliorates autoimmunity by modulating T cell imbalance via metabolic and epigenetic reprogramming
Kuniyuki Aso, Michihito Kono, Masatoshi Kanda, Yuki Kudo, Kodai Sakiyama, Ryo Hisada, Kohei Karino, Yusho Ueda, Daigo Nakazawa, Yuichiro Fujieda, Masaru Kato, Olga Amengual, Tatsuya Atsumi
Nature Communications, 14, 1, Springer Science and Business Media LLC, 2023年02月27日
研究論文（学術雑誌）, Abstract

Dysregulation of Th17 and Treg cells contributes to the pathophysiology of many autoimmune diseases. Herein, we show that itaconate, an immunomodulatory metabolite, inhibits Th17 cell differentiation and promotes Treg cell differentiation by orchestrating metabolic and epigenetic reprogramming. Mechanistically, itaconate suppresses glycolysis and oxidative phosphorylation in Th17- and Treg-polarizing T cells. Following treatment with itaconate, the S-adenosyl-L-methionine/S-adenosylhomocysteine ratio and 2-hydroxyglutarate levels are decreased by inhibiting the synthetic enzyme activities in Th17 and Treg cells, respectively. Consequently, these metabolic changes are associated with altered chromatin accessibility of essential transcription factors and key gene expression in Th17 and Treg cell differentiation, including decreased RORγt binding at the Il17a promoter. The adoptive transfer of itaconate-treated Th17-polarizing T cells ameliorates experimental autoimmune encephalomyelitis. These results indicate that itaconate is a crucial metabolic regulator for Th17/Treg cell balance and could be a potential therapeutic agent for autoimmune diseases.

Beneficial effects of nintedanib on cardiomyopathy in patients with systemic sclerosis: a pilot study.
Keita Ninagawa, Masaru Kato, Satonori Tsuneta, Suguru Ishizaka, Hideyuki Ujiie, Ryo Hisada, Michihito Kono, Yuichiro Fujieda, Yoichi M Ito, Tatsuya Atsumi
Rheumatology (Oxford, England), 62, 7, 2550, 2555, 2022年12月02日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVES: Nintedanib is an inhibitor of tyrosine kinases that has been shown to slow the progression of interstitial lung disease (ILD), including ILD associated with systemic sclerosis (SSc). The aim of this study was to explore the effect of nintedanib on cardiomyopathy associated with SSc. METHODS: Twenty consecutively hospitalized patients with SSc-ILD were enrolled and prospectively followed. The rate of change at six months in cardiac magnetic resonance (CMR) parametric mapping, including myocardial extracellular volume, was primarily evaluated. Other endpoints included changes in CMR functional parameters, echocardiographic parameters, modified Rodnan skin score, serum biomarkers, and pulmonary function test. RESULTS: Nintedanib was administered in 10 patients, whereas the other 10 were treated without nintedanib or watched, according to ILD severity and progression. Baseline values of CMR parametric mapping were not different between the two groups. The rate of change at six months in myocardial extracellular volume was largely different, almost divergent between the nintedanib group and the control group (-1.62% vs. +2.00%, p= 0.0001). Among other endpoints, the change in right ventricular ejection fraction was significantly different between the two groups (p= 0.02), with a preferential change in the nintedanib group. CONCLUSION: Our data indicate beneficial signals of nintedanib on cardiomyopathy associated with SSc. The anti-fibrotic effect of nintedanib might not be limited to the lung.

Phosphofructokinase P fine-tunes T regulatory cell metabolism, function, and stability in systemic autoimmunity.
Marc Scherlinger, Wenliang Pan, Ryo Hisada, Afroditi Boulougoura, Nobuya Yoshida, Milena Vukelic, Masataka Umeda, Suzanne Krishfield, Maria G Tsokos, George C Tsokos
Science advances, 8, 48, eadc9657, 2022年12月02日, ［国際誌］
英語, 研究論文（学術雑誌）, Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by defective regulatory T (Treg) cells. Here, we demonstrate that a T cell-specific deletion of calcium/calmodulin-dependent protein kinase 4 (CaMK4) improves disease in B6.lpr lupus-prone mice and expands Treg cells. Mechanistically, CaMK4 phosphorylates the glycolysis rate-limiting enzyme 6-phosphofructokinase, platelet type (PFKP) and promotes aerobic glycolysis, while its end product fructose-1,6-biphosphate suppresses oxidative metabolism. In Treg cells, a CRISPR-Cas9-enabled Pfkp deletion recapitulated the metabolism of Camk4-/- Treg cells and improved their function and stability in vitro and in vivo. In SLE CD4+ T cells, PFKP enzymatic activity correlated with SLE disease activity and pharmacologic inhibition of CaMK4-normalized PFKP activity, leading to enhanced Treg cell function. In conclusion, we provide molecular insights in the defective metabolism and function of Treg cells in SLE and identify PFKP as a target to fine-tune Treg cell metabolism and thereby restore their function.

Role of Glutaminase 2 in Promoting CD4+ T Cell Production of Interleukin-2 by Supporting Antioxidant Defense in Systemic Lupus Erythematosus.
Ryo Hisada, Nobuya Yoshida, Seo Yeon K Orite, Masataka Umeda, Catalina Burbano, Marc Scherlinger, Michihito Kono, Suzanne Krishfield, George C Tsokos
Arthritis & rheumatology (Hoboken, N.J.), 74, 7, 1204, 1210, 2022年07月, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: Glutaminase (GLS) isoenzymes GLS1 and GLS2 catalyze the first step of glutaminolysis. GLS1 is requisite for Th17 cell differentiation, and its inhibition suppresses autoimmune disease in animals, but the function of GLS2 is not known. The aim of this study was to investigate the role of GLS2 in CD4+ T cell function and systemic lupus erythematosus (SLE) pathogenesis. METHODS: We measured reactive oxygen species (ROS) levels, lipid peroxidation, and mitochondrial mass and polarization by flow cytometry, interleukin-2 (IL-2) production by a dual luciferase assay, and CpG DNA methylation of Il2 by a real-time polymerase chain reaction system. The impact of the overexpression of wild-type GLS1, wild-type GLS2, or mutated GLS2 at the PDZ domain-binding motif in CD4+ T cells was examined. Furthermore, GLS2 expression in CD4+ T cells from lupus-prone mice and patients with SLE was analyzed by Western blotting. RESULTS: GLS2, but not GLS1, reduced ROS levels and lipid peroxidation and restored mitochondrial function in T cells. GLS2 promoted IL-2 production through the demethylation of the Il2 promoter. Mutation of the PDZ domain-binding motif abated the ability of GLS2 to regulate IL-2 and ROS levels. In lupus-prone mice and patients with SLE, the expression of GLS2 was decreased in CD4+ T cells. Finally, GLS2 overexpression corrected ROS levels and restored IL-2 production by CD4+ T cells from lupus-prone mice and SLE patients. CONCLUSION: Our findings suggest that GLS2 has a crucial role in IL-2 production by CD4+ T cells by supporting antioxidant defense, and they offer a new approach to correcting IL-2 production by T cells in SLE.

Intertwined pathways of complement activation command the pathogenesis of lupus nephritis.
Abhigyan Satyam, Ryo Hisada, Rhea Bhargava, Maria G Tsokos, George C Tsokos
Translational research : the journal of laboratory and clinical medicine, 245, 18, 29, 2022年07月, ［国際誌］
英語, 研究論文（学術雑誌）, The complement system is involved in the origin of autoimmunity and systemic lupus erythematosus. Both genetic deficiency of complement components and excessive activation are involved in primary and secondary renal diseases, including lupus nephritis. Among the pathways, the classical pathway has long been accepted as the main pathway of complement activation in systemic lupus erythematosus. However, more recent studies have shown the contribution of factors B and D which implies the involvement of the alternative pathway. While there is evidence on the role of the lectin pathway in systemic lupus erythematosus, it is yet to be demonstrated whether this pathway is protective or harmful in lupus nephritis. Complement is being explored for the development of disease biomarkers and therapeutic targeting. In the current review we discuss the involvement of complement in lupus nephritis.

The deacetylase SIRT2 contributes to autoimmune disease pathogenesis by modulating IL-17A and IL-2 transcription.
Ryo Hisada, Nobuya Yoshida, Masataka Umeda, Catalina Burbano, Rhea Bhargava, Marc Scherlinger, Michihito Kono, Vasileios C Kyttaris, Suzanne Krishfield, George C Tsokos
Cellular & molecular immunology, 19, 6, 738, 750, 2022年06月, ［国際誌］
英語, 研究論文（学術雑誌）, Aberrant IL-17A expression together with reduced IL-2 production by effector CD4+ T cells contributes to the pathogenesis of systemic lupus erythematosus (SLE). Here, we report that Sirtuin 2 (SIRT2), a member of the family of NAD+-dependent histone deacetylases, suppresses IL-2 production by CD4+ T cells while promoting their differentiation into Th17 cells. Mechanistically, we show that SIRT2 is responsible for the deacetylation of p70S6K, activation of the mTORC1/HIF-1α/RORγt pathway and induction of Th17-cell differentiation. Additionally, SIRT2 was shown to be responsible for the deacetylation of c-Jun and histones at the Il-2 gene, resulting in decreased IL-2 production. We found that the transcription factor inducible cAMP early repressor (ICER), which is overexpressed in T cells from people with SLE and lupus-prone mice, bound directly to the Sirt2 promoter and promoted its transcription. AK-7, a SIRT2 inhibitor, limited the ability of adoptively transferred antigen-specific CD4+ T cells to cause autoimmune encephalomyelitis in mice and limited disease in lupus-prone MRL/lpr mice. Finally, CD4+ T cells from SLE patients exhibited increased expression of SIRT2, and pharmacological inhibition of SIRT2 in primary CD4+ T cells from patients with SLE attenuated the ability of these cells to differentiate into Th17 cells and promoted the generation of IL-2-producing T cells. Collectively, these results suggest that SIRT2-mediated deacetylation is essential in the aberrant expression of IL-17A and IL-2 and that SIRT2 may be a promising molecular target for new SLE therapies.

Novel susceptibility loci for steroid-associated osteonecrosis of the femoral head in systemic lupus erythematosus.
Hiroyuki Suetsugu, Kwangwoo Kim, Takuaki Yamamoto, So-Young Bang, Yuma Sakamoto, Jung-Min Shin, Nobuhiko Sugano, Ji Soong Kim, Masaya Mukai, Yeon-Kyung Lee, Koichiro Ohmura, Dae Jin Park, Daisuke Takahashi, Ga-Young Ahn, Kohei Karino, Young-Chang Kwon, Tomoya Miyamura, Jihye Kim, Junichi Nakamura, Goro Motomura, Takeshi Kuroda, Hiroaki Niiro, Takeshi Miyamoto, Tsutomu Takeuchi, Katsunori Ikari, Koichi Amano, Yoshifumi Tada, Ken Yamaji, Masato Shimizu, Takashi Atsumi, Taisuke Seki, Yoshiya Tanaka, Toshikazu Kubo, Ryo Hisada, Tomokazu Yoshioka, Mihoko Yamazaki, Tamon Kabata, Tomomichi Kajino, Yoichi Ohta, Takahiro Okawa, Yohei Naito, Ayumi Kaneuji, Yuji Yasunaga, Kenji Ohzono, Kohei Tomizuka, Masaru Koido, Koichi Matsuda, Yukinori Okada, Akari Suzuki, Bong-Jo Kim, Yuta Kochi, Hye-Soon Lee, Shiro Ikegawa, Sang-Cheol Bae, Chikashi Terao
Human molecular genetics, 31, 7, 1082, 1095, 2022年03月31日, ［国際誌］
英語, 研究論文（学術雑誌）, Osteonecrosis of the femoral head (ONFH) involves necrosis of bone and bone marrow of the femoral head caused by ischemia with unknown etiology. Previous genetic studies on ONFH failed to produce consistent results, presumably because ONFH has various causes with different genetic backgrounds and the underlying diseases confounded the associations. Steroid-associated ONFH (S-ONFH) accounts for one-half of all ONFH, and systemic lupus erythematosus (SLE) is a representative disease underlying S-ONFH. We performed a genome-wide association study (GWAS) to identify genetic risk factors for S-ONFH in patients with SLE. We conducted a two-staged GWAS on 636 SLE patients with S-ONFH and 95 588 non-SLE controls. Among the novel loci identified, we determined S-ONFH-specific loci by comparing allele frequencies between SLE patients without S-ONFH and non-SLE controls. We also used Korean datasets comprising 148 S-ONFH cases and 37 015 controls to assess overall significance. We evaluated the functional annotations of significant variants by in silico analyses. The Japanese GWAS identified 4 significant loci together with 12 known SLE susceptibility loci. The four significant variants showed comparable effect sizes on S-ONFH compared with SLE controls and non-SLE controls. Three of the four loci, MIR4293/MIR1265 [odds ratio (OR) = 1.99, P-value = 1.1 × 10-9)], TRIM49/NAALAD2 (OR = 1.65, P-value = 4.8 × 10-8) and MYO16 (OR = 3.91, P-value = 4.9 × 10-10), showed significant associations in the meta-analysis with Korean datasets. Bioinformatics analyses identified MIR4293, NAALAD2 and MYO16 as candidate causal genes. MIR4293 regulates a PPARG-related adipogenesis pathway relevant to S-ONFH. We identified three novel susceptibility loci for S-ONFH in SLE.

ADAM9 enhances Th17 cell differentiation and autoimmunity by activating TGF-β1.
Masataka Umeda, Nobuya Yoshida, Ryo Hisada, Catalina Burbano, Seo Yeon K Orite, Michihito Kono, Vasileios C Kyttaris, Suzanne Krishfield, Caroline A Owen, George C Tsokos
Proceedings of the National Academy of Sciences of the United States of America, 118, 18, 2021年05月04日, ［国際誌］
英語, 研究論文（学術雑誌）, The a disintegrin and metalloproteinase (ADAM) family of proteinases alter the extracellular environment and are involved in the development of T cells and autoimmunity. The role of ADAM family members in Th17 cell differentiation is unknown. We identified ADAM9 to be specifically expressed and to promote Th17 differentiation. Mechanistically, we found that ADAM9 cleaved the latency-associated peptide to produce bioactive transforming growth factor β1, which promoted SMAD2/3 phosphorylation and activation. A transcription factor inducible cAMP early repressor was found to bind directly to the ADAM9 promoter and to promote its transcription. Adam9-deficient mice displayed mitigated experimental autoimmune encephalomyelitis, and transfer of Adam9-deficient myelin oligodendrocyte globulin-specific T cells into Rag1 -/- mice failed to induce disease. At the translational level, an increased abundance of ADAM9 levels was observed in CD4+ T cells from patients with systemic lupus erythematosus, and ADAM9 gene deletion in lupus primary CD4+ T cells clearly attenuated their ability to differentiate into Th17 cells. These findings revealed that ADAM9 as a proteinase provides Th17 cells with an ability to activate transforming growth factor β1 and accelerates its differentiation, resulting in aberrant autoimmunity.

Incidence and risk of antiresorptive agent-related osteonecrosis of the jaw (ARONJ) after tooth extraction in patients with autoimmune disease.
Yuichiro Fujieda, Mototsugu Doi, Takuya Asaka, Masahiro Ota, Ryo Hisada, Naoki Ohnishi, Michihiro Kono, Hiraku Kameda, Daigo Nakazawa, Masaru Kato, Olga Amengual, Masahiko Takahata, Shinsuke Yasuda, Yoshimasa Kitagawa, Tatsuya Atsumi
Journal of bone and mineral metabolism, 38, 4, 581, 588, 2020年07月, ［国内誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) is a rare but serious complication in patients receiving antiresorprtive agents (AR). However, the incidence of ARONJ after tooth extraction in patients with autoimmune disease (AID) remains unclear. The present study aimed to clarify the high-risk population of ARONJ in patients with AID. MATERIALS AND METHODS: The study population comprised 232 patients treated with AR, AID or non-AID, who had undergone dental extraction from January 2011 to September 2017. The incidence and risk factors of ARONJ were analysed retrospectively. Additionally, the relationship between ARONJ and osteoporotic fracture (OF) and AR discontinuation during dental procedures was investigated. RESULTS: Of 232 patients, 10 developed ARONJ within 1 year of dental extraction. The incidence of ARONJ in patients with AID was higher than that in non-AID patients (2.0/100 person-year vs 0.5/100 person-year; p = 0.03). Among the AID patients, RA patients had strikingly high incidence of ARONJ (3.6/100 person-year). The incidence of neither ARONJ nor OF significantly differed between patients who continued and discontinued AR in the perioperative period. CONCLUSION: Patients with AID who undergo dental extraction are at high risk of ARONJ. Discontinuation of AR would not significantly contribute to reduce the incidence of ARONJ in those patients.

Autophagy promotes citrullination of VIM (vimentin) and its interaction with major histocompatibility complex class II in synovial fibroblasts.
Eri Sugawara, Masaru Kato, Yuki Kudo, Wenshi Lee, Ryo Hisada, Yuichiro Fujieda, Kenji Oku, Toshiyuki Bohgaki, Olga Amengual, Shinsuke Yasuda, Tomohiro Onodera, Shigetsugu Hatakeyama, Tatsuya Atsumi
Autophagy, 16, 5, 946, 955, 2020年05月, ［国際誌］
英語, 研究論文（学術雑誌）, We aimed to investigate the involvement of macroautophagy/autophagy in autoimmunity in rheumatoid arthritis (RA) through citrullination of VIM (vimentin) and its interaction with MHC class II in synovial fibroblasts (SFs). The cell surface expression of MHC class II and B7 costimulatory molecules on SFs was analyzed by flow cytometry after treatment with IFNG/IFN-γ (interferon gamma). Intracellular citrullinated autoantigens in SFs were analyzed by immunoblotting using serum from anti-citrullinated peptide antibodies (ACPA)-positive patient as a primary antibody. SFs were incubated in serum-free medium or treated with proteasome inhibitor MG132 to induce autophagy. An autophagy inhibitor 3-methyladenin (3-MA) was used. Intracellular citrullinated VIM (cVIM) was evaluated by immunoblotting and immunocytochemistry. The interaction between MHC class II and cVIM was evaluated with co-immunoprecipitation and proximity ligation assay (PLA). We demonstrated that MHC class II, CD274/B7-H1 and PDCD1LG2/B7-DC were expressed on SFs following treatment with IFNG whereas CD276/B7-H3 was detected on SFs regardless of the presence of IFNG. ACPA-positive sera recognized a 54 kDa protein in SFs. By immunoprecipitation, the 54 kDa protein recognized by RA sera was revealed to be cVIM. Following induction of autophagy, intracellular cVIM was increased in SFs but the effect was canceled by 3-MA. The interaction between MHC class II and cVIM was demonstrated by co-immunoprecipitation. Furthermore, PLA revealed the significant increase of MHC class II-cVIM interaction following induction of autophagy. Our findings suggest that SFs may contribute to the autoimmunity in RA through citrullination of VIM and its interaction with MHC class II promoted by autophagy.Abbreviations: 3-MA: 3-methyladenine; ACPA: anti-citrullinated peptide antibodies; anti-CCP: anti-cyclic citrullinated peptide antibody; cVIM: citrullinated VIM; BECN1: beclin1; DAPI: 4',6-diamidino-2-phenylindole; FBS: fetal bovine serum; HLA: human leukocyte antigen; IFNG/IFN-γ: interferon gamma; IL6: interleukin 6; IP: immunoprecipitation; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFI: mean fluorescence index; MHC: major histocompatibility complex; OA: osteoarthritis; PADI: peptidyl arginine deiminase; PepA: pepstatin A; PBS: phosphate-buffered saline; PtdIns3K: phosphatidylinositol 3-kinase; RA: rheumatoid arthritis; SFs: synovial fibroblasts; siRNA: small interfering RNA; VIM: vimentin.

Anti-cyclic citrullinated peptide antibody titers decrease in rheumatoid arthritis patients treated with tocilizumab: A pilot study.
Atsushi Noguchi, Shinsuke Yasuda, Ryo Hisada, Masaru Kato, Kenji Oku, Toshiyuki Bohgaki, Miho Suzuki, Yoshihiro Matsumoto, Tatsuya Atsumi
Modern rheumatology, 30, 2, 276, 281, 2020年03月, ［国際誌］
英語, 研究論文（学術雑誌）, Objectives: To analyze the effects of tocilizumab on peripheral B-cell subpopulation and its ability to produce anti-cyclic citrullinated peptide (CCP) antibody in patients with rheumatoid arthritis (RA).Methods: Thirteen consecutive RA patients initiated with tocilizumab were enrolled in our prospective study. Anti-CCP antibody titers and clinical parameters were evaluated during treatment. Peripheral blood B-cell subsets were analyzed using flow cytometry according to the Human Immunology Project.Results: Disease activity was significantly improved and anti-CCP antibody titers significantly decreased at week 24 compared to baseline. The percentages of post-switch memory B cells in CD19+ cells transiently increased at week 12, but there was no significant difference in any of the investigated B-cell subpopulations at week 24 compared to baseline. The ratios of post-switch memory to naïve B cells (post-switch/naïve) correlated negatively with anti-CCP antibody titers regardless of the time-points.Conclusion: Our study indicated that tocilizumab has a potential to reduce anti-CCP antibody production presumably by affecting post-switch/naïve ratio, and that anti-CCP antibody titers reflect B-cell distribution/subpopulation. As anti-CCP antibodies are produced in lymph nodes or ectopic lymphoid structures in synovial tissues, not in circulation, transient increment of post-switch memory B cells after tocilizumab treatment may reflect the altered balance of B-cell distribution between circulation and arthritic joints, resulting in suppressed production of anti-CCP antibody in situ.

Circulating plasmablasts contribute to antiphospholipid antibody production, associated with type I interferon upregulation.
Ryo Hisada, Masaru Kato, Eri Sugawara, Masatoshi Kanda, Yuichiro Fujieda, Kenji Oku, Toshiyuki Bohgaki, Olga Amengual, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi
Journal of thrombosis and haemostasis : JTH, 17, 7, 1134, 1143, 2019年07月, ［国際誌］
英語, 研究論文（学術雑誌）, Essentials The mechanism of antiphospholipid antibodies (aPL) production remains unclear. We investigated lymphocyte subset, single nucleotide polymorphisms (SNP), and aPL-producing cells. The increase of circulating plasmablasts was associated with type I interferon upregulation. Our novel ex vivo assay revealed circulating plasmablasts as a major source of aPL. SUMMARY: Background/objective Antiphospholipid antibodies (aPL) are pathogenic autoantibodies in antiphospholipid syndrome (APS). This study aimed to clarify the mechanism of aPL production. Methods T cell and B cell subsets were evaluated in peripheral blood mononuclear cells (PBMCs) of 26 primary APS (PAPS), 19 systemic lupus erythematosus-associated APS (SLE/APS) patients and 10 healthy controls. The SLE-related or APS-related single nucleotide polymorphisms (SNP) were analyzed in those patients. Interferon (IFN) score was calculated based on the mRNA expression of Ly6e, Mx1, IFIT1, and IFIT3 in PBMCs. The PBMCs obtained from APS patients were cultured ex vivo following depletion of CD20 positive or negative B cells and the culture supernatants were applied to aPL measurements. Results In PAPS and SLE/APS patients, Th2, Th17, and plasmablasts were increased while regulatory T, memory B, and regulatory B cells were decreased compared to healthy controls. Genetic analysis revealed that the increase of plasmablasts was more pronounced in patients carrying a risk allele of toll like receptor (TLR) 7 SNP rs3853839. The IFN score was significantly higher in the risk allele carriers. Ex vivo experiments showed that aPL were present in the culture supernatant of PBMCs lacking CD20+CD19+ subset, but not in that of cells lacking CD20-CD19+ subset. Conclusions Our data indicate an important role of plasmablasts in the production of aPL. Furthermore, the increase of plasmablasts was associated with TLR 7 and type I IFN, suggesting a common pathophysiology in SLE and APS. Targeting plasmablasts might be a novel immunological therapeutic approach in the treatment of APS.

Efficacy of dual antiplatelet therapy for preventing recurrence of arterial thrombosis in patients with antiphospholipid syndrome.
Naoki Ohnishi, Yuichiro Fujieda, Ryo Hisada, Hiroyuki Nakamura, Masaru Kato, Kenji Oku, Toshiyuki Bohgaki, Olga Amengual, Shinsuke Yasuda, Tatsuya Atsumi
Rheumatology (Oxford, England), 58, 6, 969, 974, 2019年06月01日, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: Warfarin is regarded as the standard treatment for preventing thrombotic events in APS, but the recurrence rate is still high. Dual antiplatelet therapy (DAPT) has been shown to be effective for the prevention of acute coronary syndrome or stroke. The objective of this study was to evaluate the efficacy of DAPT for the prevention of thrombosis recurrence in APS patients with history of arterial thrombosis. METHODS: This retrospective cohort study of APS patients was conducted at Hokkaido University Hospital between 1990 and 2016. The secondary prophylactic effects and safety of warfarin monotherapy (Wf), antiplatelet monotherapy (AP), warfarin and antiplatelet combination therapy (Wf + AP) and DAPT were evaluated. The primary endpoints were set as thrombosis-free and adverse events-free survival period. Adverse events were defined as severe bleeding and death. RESULTS: A total of 90 APS patients were enrolled. Thrombotic recurrence was found in 40 patients (35 arterial and 5 venous thromboses) and serious adverse events in 20 patients (9 severe bleeding events and 14 deaths). Kaplan-Meier analysis demonstrated a 10-year recurrence-free survival rate of 62%. The recurrence rate per 100 patient-years was as follows: Wf: 11.6, AP: 5.5, Wf: + AP: 3.7, DAPT: 1.8. We demonstrated that DAPT significantly reduced the rate of recurrence compared with Wf (log-rank P = 0.001). There were no significant differences in the rate of serious adverse events among the groups. CONCLUSION: DAPT might be considered as an effective and safe option for the prophylaxis of recurrent arterial thrombosis in APS.

Pathogenic roles of anti-C1q antibodies in recurrent pregnancy loss.
Kazumasa Ohmura, Kenji Oku, Tamao Kitaori, Olga Amengual, Ryo Hisada, Masatoshi Kanda, Yuka Shimizu, Yuichiro Fujieda, Masaru Kato, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Mayumi Sugiura-Ogasawara, Tatsuya Atsumi
Clinical immunology (Orlando, Fla.), 203, 37, 44, 2019年06月, ［国際誌］
英語, 研究論文（学術雑誌）, Recurrent pregnancy loss (RPL) is often considered idiopathic, however excessive complement activation has been observed in pregnancy related manifestations. Anti-C1q antibodies (anti-C1q) are associated with the activation of complement pathway in lupus patients, while it remains unclear in RPL. Firstly, we showed that both the prevalence and titre of anti-C1q were significantly higher in unexplained RPL than in healthy parous individuals. Secondly, we established the murine model of anti-C1q induced pregnancy loss using a monoclonal anti-mouse C1q antibody, JL-1. In mice treated with JL-1, high ratio of pregnancy loss and fetal growth restriction were frequently observed and complement activation occurred. C5a receptor (C5aR) blockade cancelled these pathogenic changes in mice treated with JL-1. In conclusion, our study reveals an association between the prevalence of anti-C1q and RPL. Additionally, our murine model has indicated that anti-C1q can induce reproductive failure, which might be ameliorated by therapy targeting the C5-C5aR axis.

Antiphospholipid score is a novel risk factor for idiopathic osteonecrosis of the femoral head in patients with systemic lupus erythematosus.
Ryo Hisada, Masaru Kato, Naoki Ohnishi, Eri Sugawara, Yuichiro Fujieda, Kenji Oku, Toshiyuki Bohgaki, Olga Amengual, Shinsuke Yasuda, Tatsuya Atsumi
Rheumatology (Oxford, England), 58, 4, 645, 649, 2019年04月01日, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: Idiopathic osteonecrosis of the femoral head (ION) is a common complication of SLE associated with CS therapy. Although the pathogenesis of ION involves local bone ischaemia favoured by thrombophilia, the involvement of aPL in lupus ION remains to be elucidated. We have previously reported the aPL score (aPL-S) as a quantitative marker of aPL and the development of thrombotic events in autoimmune diseases. The aim of this study was to identify the impact of aPL on the development of ION using aPL-S. METHODS: This was a single-centre retrospective study comprising 88 consecutive SLE patients who underwent MRI of the hip joints from January 2000 to March 2017. Baseline characteristics, pharmacotherapy and total hip arthroplasty performed during follow-up were evaluated. RESULTS: The presence of ION was confirmed by MRI scan in 38 patients (43.1%). Male gender, positivity of any aPL, aPL-S, high aPL-S (≥30) and high dose of CS were identified as risk factors for ION by univariate analysis. Multivariate analysis revealed high aPL-S (odds ratio 5.12, 95% CI 1.18-29.79) and use of high-dose CS (odds ratio 10.25, 95% CI 3.00-48.38) as independent variables. Kaplan-Meier analysis showed that patients with high aPL-S received total hip arthroplasty more frequently than those without aPL (P = 0.010). CONCLUSIONS: We newly identified high aPL-S as an important risk factor for ION development in SLE, suggesting the involvement of aPL-induced coagulopathy in the pathophysiology of lupus ION.

Clinical profiles and risk assessment in patients with antiphospholipid antibodies.
Masaru Kato, Ryo Hisada, Tatsuya Atsumi
Expert review of clinical immunology, 15, 1, 73, 81, 2019年01月, ［国際誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: Antiphospholipid syndrome (APS) is an acquired autoimmune thrombophilia associated with the presence of persistent antiphospholipid antibodies (aPL). Owing to recent studies, not only APS patients but also incidentally-identified, asymptomatic aPL carriers are able to be stratified in terms of the risk of future thrombotic events, according to the variety and the titer of positive aPL tests and to the non-thrombotic, aPL-associated clinical manifestations. Areas covered: Here, we critically review (1) criteria manifestations of APS, (2) non-criteria manifestations of APS, (3) risk assessment in patients with APS and in aPL carriers, and (4) the potential role of primary thrombosis prophylaxis in aPL carriers. In addition, we discuss what we are currently able to do and what we need to do in the future for primary prophylaxis against a first thrombotic event. Expert commentary: We suggest a comprehensive algorithm to stratify thrombotic risk in aPL carriers, including criteria aPL, non-criteria aPL, their scoring systems, and non-criteria manifestations. However, further studies, particularly prospective randomized controlled trials, are highly warranted to establish an effective and tolerable treatment regimen for high risk aPL carriers.

Clinical significance of plasma presepsin levels in patients with systemic lupus erythematosus.
Shun Tanimura, Yuichiro Fujieda, Michihiro Kono, Yuhei Shibata, Ryo Hisada, Eri Sugawara, Hiroyuki Nakamura, Kazumasa Ohmura, Sanae Shimamura, Asako Mitani, Haruki Shida, Toshiyuki Watanabe, Masaru Kato, Kenji Oku, Toshiyuki Bohgaki, Olga Amengual, Shinsuke Yasuda, Chikara Shimizu, Tatsuya Atsumi
Modern rheumatology, 28, 5, 865, 871, 2018年09月, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVES: Presepsin (PSEP: soluble CD14 subtype) is produced from bacteria-stimulated monocytes or neutrophils, thus recognized as a biomarker of sepsis. Aberrant functions in monocyte or neutrophils are increasingly recognized in systemic lupus erythematosus (SLE). We investigated whether plasma PSEP reflects disease activity in patients with SLE. METHODS: This retrospective study comprised 35 patients with SLE and 72 with non-SLE autoimmune diseases who visited our facility during the period from August 2012 to September 2015. Plasma PSEP levels and laboratory data were compared between SLE and non-SLE. Clinical markers of SLE disease activity, including SLE disease activity index 2000 (SLEDAI-2K), serum complement concentrations and serum anti-ds-DNA antibodies were assessed in correlation with plasma PSEP levels. RESULTS: Plasma PSEP levels in SLE were higher than those in non-SLE. This phenomenon holds true when comparing SLE and non-SLE patients in the absence of infection (p = .0008). Plasma PSEP levels in SLE patients negatively correlated with C3 (r = -0.4454, p = .0430), CH50 (r = -0.4502, p = .0406) and positively with SLEDAI-2K (r = 0.4801, p = .0237). CONCLUSION: Elevated plasma PSEP levels were correlated with disease activity of SLE, suggesting inappropriate monocyte or neutrophil activation in the pathophysiology of SLE exacerbation.

Effects of statins on thrombosis development in patients with systemic lupus erythematosus and antiphospholipid antibodies
T. Watanabe, K. Oku, O. Amengual, R. Hisada, K. Ohmura, I. Nakagawa, H. Shida, T. Bohgaki, T. Horita, S. Yasuda, T. Atsumi
Lupus, 27, 2, 225, 234, SAGE Publications Ltd, 2018年02月01日, ［査読有り］
英語, 研究論文（学術雑誌）, The objective of this study is to identify the effects of statins and risk factors for thrombosis in patients with new onset of systemic lupus erythematosus (SLE) with or without antiphospholipid antibodies (aPL). Consecutive patients with SLE without history of thrombotic events were retrospectively enrolled from April 1997 to February 2014. The development of first thrombosis and death caused by thrombosis were defined as the study endpoint. Risk and protective factors for developing thrombosis were analyzed. A total of 152 patients, 80 positive and 72 negative for aPL, were included. In aPL-positive patients, 15 developed arterial (n = 6) and venous (n = 9) thrombosis (median follow-up period 69 months). Cox’s proportional hazards model showed that older age at SLE onset and IgG-anticardiolipin antibodies (aCL) were statistically significant risks for thrombosis. Statin therapy was identified as a statistically significant protective factor against thrombosis (hazard ratio 0.12, 95% confidence interval 0.01–0.98). In aPL-negative patients (median follow-up period 46 months), seven patients developed thrombosis (five arterial and two venous). No risk factors for thrombosis were found in this group. In aPL-positive patients with SLE, the late disease onset and the presence of IgG-aCL represented additional risk factors for thrombosis. Statin treatment appeared as a protective factor for thrombosis.

Treatment of Vasodilator-resistant Mixed Connective Tissue Disease-associated Pulmonary Arterial Hypertension with Glucocorticoid and Cyclophosphamide.
Eri Sugawara, Masaru Kato, Ryo Hisada, Kenji Oku, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi
Internal medicine (Tokyo, Japan), 56, 4, 445, 448, 2017年, ［国内誌］
英語, 研究論文（学術雑誌）, Pulmonary arterial hypertension (PAH) associated with systemic lupus erythematosus (SLE) or mixed connective tissue disease (MTCD), in contrast to other types of PAH, may respond to immunosuppressive therapy. Most PAH cases with an immunosuppressant response were in the early stages of the disease (WHO functional class III or less). The present case was a 34-year-old woman with MCTD-associated PAH (WHO functional class IV) who was resistant to a combination of three vasodilators. Afterwards, she was treated with glucocorticoid and cyclophosphamide. This case suggested the potential benefit of immunosuppressants in patients with severe MCTD-associated PAH.

Post-steroid neuropsychiatric manifestations are significantly more frequent in SLE compared with other systemic autoimmune diseases and predict better prognosis compared with de novo neuropsychiatric SLE.
Yuka Shimizu, Shinsuke Yasuda, Yuki Kako, Shin Nakagawa, Masatoshi Kanda, Ryo Hisada, Kazumasa Ohmura, Sanae Shimamura, Haruki Shida, Yuichiro Fujieda, Masaru Kato, Kenji Oku, Toshiyuki Bohgaki, Tetsuya Horita, Ichiro Kusumi, Tatsuya Atsumi
Autoimmunity reviews, 15, 8, 786, 94, 2016年08月, ［国際誌］
英語, 研究論文（学術雑誌）, In patients with systemic lupus erythematosus (SLE), neuropsychiatric (NP) symptoms sometimes occur after administration of corticosteroids, making differential diagnosis between NPSLE and steroid-induced psychosis challenging for clinicians. The aim of this study was to clarify the characteristics of post-steroid NP disease (PSNP) in patients with SLE. Clinical courses of 146 patients with SLE and 162 with other systemic autoimmune diseases, all in the absence of NP manifestations on admission, were retrospectively analyzed. Forty-three NPSLE patients on admission (de novo NPSLE) were also investigated. All patients were consecutively recruited and treated with 40mg/day or more of prednisolone in Hokkaido University Hospital between April 2002 and March 2015. The prevalence of PSNP was strikingly higher in SLE patients than other systemic autoimmune diseases (24.7% vs. 7.4%, OR 4.09, 95% CI 2.04-8.22). As independent risk factors to develop PSNP in SLE patients, past history of mental disorder and the presence of antiphospholipid syndrome were identified using multiple logistic regression analysis. In patients with PSNP-SLE, mood disorder was significantly more frequent than in de novo NPSLE (47.2% vs. 20.9%, OR 3.38, 95% CI 1.26-9.04). Of PSNP-SLE patients, two-thirds were with one or more abnormal findings in cerebrospinal fluid, electroencephalogram, MRI or SPECT. Majority of our PSNP-SLE patients received intensified immunosuppressive treatments and experienced improvement in most cases. PSNP-SLE had better relapse-free survival than de novo NPSLE (p<0.05, log rank test). In conclusion, PSNP frequently occurred in patients with SLE and treated successfully with immunosuppressive therapy, indicating that NPSLE is likely to harbor patients with PSNP-SLE.

Autoantibodies against a complement component 1 q subcomponent contribute to complement activation and recurrent thrombosis/pregnancy morbidity in anti-phospholipid syndrome.
Kenji Oku, Olga Amengual, Ryo Hisada, Kazumasa Ohmura, Ikuma Nakagawa, Toshiyuki Watanabe, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi
Rheumatology (Oxford, England), 55, 8, 1403, 11, 2016年08月, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: To investigate the prevalence and significance of the autoantibodies against complement component 1 q subcomponent (C1q) in patients with APS. METHODS: In all, 40 consecutive primary APS patients, 42 patients with non-SLE CTDs and 20 SLE patients negative for aPL were enrolled in this retrospective analysis. Refractory APS was defined as a clinical status of recurring thrombosis or pregnancy morbidity during adequate secondary prophylaxis. An ELISA was used to measure serum levels of anti-C1q antibodies and anaphylatoxins (C3a, C4a). RESULTS: Anti-C1q antibodies were found in 36% (15/42) and 2.5% (1/40) of primary APS patients and controls, respectively. Among primary APS patients, anti-C1q antibody titres were significantly correlated with serum C4a levels (P = 0.013). Neither the prevalence nor the titre of anti-C1q antibodies was associated with any specific clinical manifestations of APS, nor titres of aPL. Refractory APS patients (n = 10) had a higher prevalence of anti-C1q antibodies (9/10 vs 6/32, P = 0.01) than APS patients without recurrence (n = 32). CONCLUSION: Anti-C1q antibodies are associated with complement activation in APS and may contribute to the pathogenesis, particularly in refractory cases.

Markers of thrombotic events in autoimmune diseases: Comparison of Antiphospholipid Score (aPL-S) and Global Anti-phospholipid Syndrome Score (GAPSS)
Kenji Oku, Olga Amengual, Hiroyuki Nakamura, Ryo Hisada, Kazumasa Oomura, Masaru Mato, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi
JOURNAL OF REPRODUCTIVE IMMUNOLOGY, 112, 129, 130, ELSEVIER IRELAND LTD, 2015年11月, ［査読有り］
英語

Reduction of HLA Class II Expression and Beta-2-Glycoprotein I Presentation By Fluvastatin in Vitro and in Vivo: Possible Mechanism of Statin-Induced-Deprocoagulation in the Antiphospholipid Syndrome
Toshiyuki Watanabe, Kenji Oku, Olga Amengual, Ryo Hisada, Kazumasa Ohmura, Haruki Shida, Yuka Shimizu, Masaru Kato, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Akihiro Ishizu, Hisashi Arase, Tatsuya Atsumi
ARTHRITIS & RHEUMATOLOGY, 67, WILEY-BLACKWELL, 2015年10月, ［査読有り］
英語

[The function and the significance of full-automated tests for detecting antiphospholipid antibodies].
Kenji Oku, Olga Amengual, Ryo Hisada, Kazumasa Oomura, Ikuma Nakagawa, Toshiyuki Watanabe, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi
Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology, 38, 3, 157, 63, 2015年, ［国内誌］
日本語, 研究論文（学術雑誌）, Antiphospholipid antibodies (aPLs) are a group of heterogenous antibodies with immunological and functional variations that are detected in the sera of patients with antiphospholipid syndrome (APS). Detection of these antibodies in an efficient and accurate manner remains a significant issue. It requires numerous immunological and functional tests, burdening the laboratory departments, and as a consequence, not sufficiently performed in many cases. We retrospectively studied a total of 212 subjects with or without collagen diseases including APS that visited the outpatients of multiple institutions (department of internal medicine at Health Science University of Hokkaido, department of medicine II and department of gastroenterology at Hokkaido University Hospital). All the subjects were measured aPL (anticardio anticardiolipin antibody IgG/IgM, anti-β2-glycoprotein I antibody IgG/IgM) using a fully automated chemiluminescence analyzer and compared measurement results with those obtained using the conventional ELISA method. These methods were found to have similar diagnostic accuracy, with κ values exceeding 0.6. Of 61 APS patients 41 (67%) were positive for two or more tests: significantly higher than other disease such as systemic lupus erythematosus (3/37, 9%) or non-SLE collagen disease (1/53, 2%). The fully automated chemiluminescence analyzer, which can simultaneously measure multiple aPLs, was thus determined to be useful for diagnosing APS.

Markers of Thrombotic Events in Autoimmune Diseases: Comparison of Antiphospholipid Score (aPL-S) and Global Anti-Phospholipid Syndrome Score (GAPSS).
Kenji Oku, Olga Amengual, Ryo Hisada, Kazumasa Oomura, Ikuma Nakagawa, Toshiyuki Watanabe, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi
ARTHRITIS & RHEUMATOLOGY, 66, S1251, S1252, WILEY-BLACKWELL, 2014年10月, ［査読有り］
英語

Thrombocytopenia in Primary Antiphospholipid Syndrome Is Related to Arterial Thrombosis
Ikuma Nakagawa, Kenji Oku, Olga Amengual, Ryo Hisada, Eri Sugawara, Kazumasa Ohmura, Tomoko Fukui, Sanae Shimamura, Haruki Shida, Toshiyuki Watanabe, Yuka Shimizu, Michihito Kono, Takashi Kurita, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi
ARTHRITIS & RHEUMATOLOGY, 66, S1, S1, WILEY-BLACKWELL, 2014年10月, ［査読有り］
英語

The Protective Effects of Statins for Thrombosis in Patients with Systemic Lupus Erythematosus Positive for Antiphospholipid Antibodies.
Toshiyuki Watanabe, Kenji Oku, Olga Amengual, Eri Sugawara, Ryo Hisada, Kazumasa Ohmura, Tomoko Fukui, Sanae Shimamura, Ikuma Nakagawa, Atsushi Noguchi, Haruki Shida, Michihito Kono, Yuka Shimizu, Takashi Kurita, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi
ARTHRITIS & RHEUMATOLOGY, 66, S1154, S1155, WILEY-BLACKWELL, 2014年10月, ［査読有り］
英語

Giant cell arteritis.
Satoshi Jodo, Ryo Hisada
Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology, 36, 6, 459, 66, 2013年, ［国内誌］
英語, 研究論文（学術雑誌）, Giant cell arteritis (GCA) is a granulomatous arteritis and it occurs older (more than 50 years) individuals. As GCA frequently involves temporal artery, this disease had been called as temporal arteritis. However, except for the temporal artery, GCA affects branches of the carotid arteries, as well as aorta and its major branches preferentially. Thus, this arteritis is collectively called as GCA from the characteristic histological findings. We systematically introduce the clinical pictures of GCA in the first half of this article. Because affected arteries of GCA are different in each patient, some patients do not present with classical clinical features, such as headache and tenderness of temporal artery. Recently, there are several variant forms of GCA have been recognized. Certain subtypes demonstrate organ dysfunction, such as visual loss or peripheral neuropathy with minimal or absent classical and systemic manifestations. This form of GCA is referred to as occult GCA. On the other hand, other form of GCA presents with a systemic inflammatory syndrome in the absence of focal ischemic symptoms. This is referred to as silent or masked GCA. In the latter half of this article, we introduce two patients presenting with such atypical presentations. One could be diagnosed as occult GCA, and the other was diagnosed as silent GCA with large vessel type. GCA is a heterogenous disease with more than a single clinical picture. This article can provide considerations of the wide spectrum of presentation of this characteristic systemic arteritis.

Deviation of T and B Cell Subset and Its Association with Single Nucleotide Polymorphisms in Patients with Antiphospholipid Syndrome
Ryo Hisada, Masaru Kato, Hisako Nakagawa, Eri Sugawara, Masatoshi Kanda, Kazumasa Ohmura, Ikuma Nakagawa, Kenji Oku, Toshiyuki Bohgaki, Olga Amengual, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi, ARTHRITIS & RHEUMATOLOGY, 68, 2016年10月
WILEY, 英語, 研究発表ペーパー・要旨（国際会議）

Preventive Effect of Combined Treatment with Bisphosphonate and Vitamin D on Atherosclerosis in Patients with Systemic Lupus Erythematosus
Kazumasa Ohmura, Masaru Kato, Toshiyuki Watanabe, Ryo Hisada, Masatoshi Kanda, Sanae Shimamura, Ikuma Nakagawa, Yuka Shimizu, Kenji Oku, Toshiyuki Bohgaki, Olga Amengual, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi, ARTHRITIS & RHEUMATOLOGY, 68, 2016年10月
WILEY, 英語, 研究発表ペーパー・要旨（国際会議）

Anti-CCP Antibody Titers Decrease with Altered B-Cell Subpopulation in RA Patients Treated with Tocilizumab
Atsushi Noguchi, Shinsuke Yasuda, Ryo Hisada, Kazumasa Ohmura, Sanae Shimamura, Yuka Shimizu, Masaru Kato, Kenji Oku, Toshiyuki Bohgaki, Olga Amengual, Tetsuya Horita, Miho Suzuki, Yoshihiro Matsumoto, Tatsuya Atsumi, ARTHRITIS & RHEUMATOLOGY, 68, 2016年10月
WILEY, 英語, 研究発表ペーパー・要旨（国際会議）

Complement Activation in Antiphospholipid Syndrome Due to the Multi-Activated Pathways of the Complement System
Hiroyuki Nakamura, Kenji Oku, Ryo Hisada, Kazumasa Ohmura, Masaru Kato, Toshiyuki Bohgaki, Olga Amengual, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi, ARTHRITIS & RHEUMATOLOGY, 68, 2016年10月
WILEY, 英語, 研究発表ペーパー・要旨（国際会議）

Autoantibodies Against High Density Lipoprotein-Associated Proteins Are Related to Elevated Oxidized Low Density Lipoprotein Levels in Antiphospholipid Syndrome
Kenji Oku, Uhei Shibata, Joana Batuca, Olga Amengual, Michihiro Kono, Hiroyuki Nakamura, Ryo Hisada, Kazumasa Ohmura, Masaru Kato, Toshiyuki Bohgaki, Shinsuke Yasuda, Jose Delgado Alves, Tatsuya Atsumi, ARTHRITIS & RHEUMATOLOGY, 68, 2016年10月
WILEY, 英語, 研究発表ペーパー・要旨（国際会議）

全身性エリテマトーデス患者における動脈硬化進展と骨塩量との関連
大村 一将, 奥 健志, 渡邊 俊之, 谷村 瞬, 柴田 悠平, 河野 通大, 久田 諒, 菅原 恵理, 中村 浩之, 神田 真聡, 嶋村 抄苗, 清水 裕香, 加藤 将, 坊垣 暁之, 堀田 哲也, 保田 晋助, 渥美 達也, 日本臨床免疫学会会誌, 39, 4, 385, 385, 2016年08月
日本臨床免疫学会, 日本語

ループス腎炎に対する寛解導入治療におけるミコフェノール酸モフェチルの短期的治療効果
河野 通大, 保田 晋助, 尾形 裕介, 阿部 早和子, 大西 直樹, 土井 基嗣, 谷村 瞬, 柴田 悠平, 中村 浩之, 菅原 恵理, 久田 諒, 神田 真聡, 大村 一将, 嶋村 抄苗, 清水 裕香, 加藤 将, 奥 健志, 坊垣 暁之, 堀田 哲也, 渥美 達也, 日本臨床免疫学会会誌, 39, 4, 386, 386, 2016年08月
日本臨床免疫学会, 日本語