Frontiers Media Acta Medica Okayama 1664-3224 14 2023 E3-ubiquitin ligases and recent progress in osteoimmunology 1120710 EN Yosuke Asano Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences Yoshinori Matsumoto Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences Jun Wada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences Robert Rottapel Princess Margaret Cancer Center, University Health Network, University of Toronto Ubiquitin-mediated proteasomal degradation is a post-transcriptional protein modification that is comprised of various components including the 76-amino acid protein ubiquitin (Ub), Ub-activating enzyme (E1), Ub-conjugating enzyme (E2), ubiquitin ligase (E3), deubiquitinating enzyme (DUB) and proteasome. We and others have recently provided genetic evidence showing that E3-ubiquitin ligases are associated with bone metabolism, the immune system and inflammation through ubiquitylation and subsequent degradation of their substrates. Dysregulation of the E3-ubiquitin ligase RNF146-mediated degradation of the adaptor protein 3BP2 (SH3 domain-binding protein 2) causes cherubism, an autosomal dominant disorder associated with severe inflammatory craniofacial dysmorphia syndrome in children. In this review, on the basis of our discoveries in cherubism, we summarize new insights into the roles of E3-ubiquitin ligases in the development of human disorders caused by an abnormal osteoimmune system by highlighting recent genetic evidence obtained in both human and animal model studies. No potential conflict of interest relevant to this article was reported.

Public Library Science Acta Medica Okayama 1932-6203 17 6 2022 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) e0270569 EN Keigo Hayashi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken-Ei Sada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yosuke Asano Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yu Katayama Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Keiji Ohashi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Michiko Morishita Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshia Miyawaki Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Haruki Watanabe Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takayuki Katsuyama Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mariko Narazaki Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshinori Matsumoto Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Nobuyuki Yajima Department of Medicine, Division of Rheumatology, Showa University School of Medicine Ryusuke Yoshimi Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine Yasuhiro Shimojima Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine Shigeru Ohno Center for Rheumatic Diseases, Yokohama City University Medical Center Hiroshi Kajiyama Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University Kunihiro Ichinose Department of Immunology and Rheumatology, Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences Shuzo Sato Department of Rheumatology, Fukushima Medical University School of Medicine Michio Fujiwara Department of Rheumatology, Yokohama Rosai Hospital Jun Wada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences 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 diseaserelated 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/1.73m(2), 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. No potential conflict of interest relevant to this article was reported.

American Society for Clinical Investigation Acta Medica Okayama 1558-8238 132 7 2022 Tankyrase represses autoinflammation through the attenuation of TLR2 signaling e140869 EN Yoshinori Matsumoto Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ioannis D. Dimitriou Princess Margaret Cancer Centre, University Health Network, University of Toronto Jose La Rose Princess Margaret Cancer Centre, University Health Network, University of Toronto Melissa Lim Princess Margaret Cancer Centre, University Health Network, University of Toronto Susan Camilleri Centre for Modeling Human Disease, Toronto Centre for Phenogenomics Napoleon Law Centre for Modeling Human Disease, Toronto Centre for Phenogenomics Hibret A. Adissu Labcorp Early Development Laboratories Inc. Jiefei Tong Program in Cell Biology, The Hospital for Sick Children, Department of Molecular Genetics Michael F. Moran Program in Cell Biology, The Hospital for Sick Children, Department of Molecular Genetics Andrzej Chruscinski Multi-Organ Transplant Program, University Health Network Fang He Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yosuke Asano Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takayuki Katsuyama Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken-ei Sada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jun Wada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Robert Rottapel Princess Margaret Cancer Centre, University Health Network, University of Toronto 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. No potential conflict of interest relevant to this article was reported.

Frontiers Media SA. Acta Medica Okayama 2234-943X 11 2021 RUNX2 Phosphorylation by Tyrosine Kinase ABL Promotes Breast Cancer Invasion (vol 11, 665273, 2021) 729192 EN Fang He Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshinori Matsumoto Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yosuke Asano Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuriko Yamamura Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takayuki Katsuyama Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jose La Rose Princess Margaret Cancer Center, University Health Network, University of Toronto Nahoko Tomonobu Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Ni Luh Gede Yoni Komalasari Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Masakiyo Sakaguchi Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Robert Rottapel Princess Margaret Cancer Center, University Health Network, University of Toronto Jun Wada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences No potential conflict of interest relevant to this article was reported.

Frontiers Media S.A. Acta Medica Okayama 2234-943X 11 2021 RUNX2 Phosphorylation by Tyrosine Kinase ABL Promotes Breast Cancer Invasion 665273 EN Fang He Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshinori Matsumoto Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yosuke Asano Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuriko Yamamura Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takayuki Katsuyama Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jose La Rose Princess Margaret Cancer Center, University Health Network, University of Toronto Nahoko Tomonobu Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Ni Luh Gede Yoni Komalasari Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Masakiyo Sakaguchi Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Robert Rottapel Princess Margaret Cancer Center, University Health Network, University of Toronto Jun Wada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences 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. No potential conflict of interest relevant to this article was reported.

BMC Acta Medica Okayama 1478-6354 23 1 2021 Association of glucocorticoid doses and emotional health in lupus low disease activity state (LLDAS): a cross-sectional study EN Yoshia Miyawaki Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Sayaka Shimizu Institute for Health Outcome & Process Evaluation Research (i-Hope International) Yusuke Ogawa Department of Healthcare Epidemiology, School of Public Health in the Graduate School of Medicine, Kyoto University Ken-Ei Sada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yukitoshi Katayama Ushimado Marine Institute, Faculty of Science, Okayama University Yosuke Asano Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Keigo Hayashi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuriko Yamamura Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Sumie Hiramatsu-Asano Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Keiji Ohashi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Michiko Morishita Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Haruki Watanabe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Mariko Takano-Narazaki Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshinori Matsumoto Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Nobuyuki Yajima Department of Healthcare Epidemiology, School of Public Health in the Graduate School of Medicine, Kyoto University Ryusuke Yoshimi Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine Yasuhiro Shimojima Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine Shigeru Ohno Center for Rheumatic Diseases, Yokohama City University Medical Center Hiroshi Kajiyama Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University Kunihiro Ichinose Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences Shuzo Sato Department of Rheumatology, Fukushima Medical University School of Medicine Michio Fujiwara Department of Rheumatology, Yokohama Rosai Hospital Hajime Yamazaki Section of Clinical Epidemiology, Department of Community Medicine, Graduate School of Medicine, Kyoto University Yosuke Yamamoto Department of Healthcare Epidemiology, School of Public Health in the Graduate School of Medicine, Kyoto University Jun Wada Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Shunichi Fukuhara Section of Clinical Epidemiology, Department of Community Medicine, Graduate School of Medicine, Kyoto University Background While survival of systemic lupus erythematosus (SLE) patients has improved substantially, problems remain in the management of their emotional health. Medium to high-dose glucocorticoid doses are known to worsen emotional health; the effect is unclear among patients receiving relatively low-dose glucocorticoids. This study aims to investigate the association between low glucocorticoid doses and emotional health in lupus low disease activity state (LLDAS). Methods This cross-sectional study drew on data from SLE patients in 10 Japanese institutions. The participants were adult patients with SLE duration of >= 1 year who met LLDAS criteria at the study visit from April 2018 through September 2019. The exposure was the daily glucocorticoid dose (mg oral prednisolone). The outcome was the emotional health score of the lupus patient-reported outcome scale (range: 0 to 100). Multiple linear regression analysis was performed with adjustment for confounders including disease-related damage, activity, and psychotropic drug use. Results Of 192 patients enrolled, 175 were included in the analysis. Their characteristics were as follows: female, 89.7%; median age, 47 years (interquartile range (IQR): 37.0, 61.0). Median glucocorticoid dose was 4.0 mg (IQR 2.0, 5.0), and median emotional health score 79.2 (IQR 58.3, 91.7). Multiple linear regression analysis showed daily glucocorticoid doses to be associated with worse emotional health (beta coefficient = - 2.54 [95% confidence interval - 4.48 to - 0.60], P = 0.01). Conclusions Daily glucocorticoid doses were inversely associated with emotional health among SLE patients in LLDAS. Further studies are needed to determine whether glucocorticoid tapering leads to clinically significant improvements in emotional health. No potential conflict of interest relevant to this article was reported.

Lippincott, Williams & Wilkins Acta Medica Okayama 0025-7974 100 3 2021 Granulomatosis with polyangiitis with obstructive pneumonia progressing to hypertrophic pachymeningitis A case report e24028 EN Keigo Hayashi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Haruki Watanabe Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuriko Yamamura Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yosuke Asano Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yukitoshi Katayama Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Sumie Hiramatsu-Asano Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Keiji Ohashi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Michiko Morishita Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mariko Narazaki Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshinori Matsumoto Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken-Ei Sada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jun Wada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Rationale: </br> Bronchial involvement alone is a rare initial manifestation of granulomatosis with polyangiitis (GPA). Herein, we report a case of refractory GPA with obstructive pneumonia caused by bronchial involvement.</br> Patient concerns: </br> A 65-year-old man complained of a 2-week cough and fever.</br> Diagnoses: </br> Considering the presence of opacities and multiple consolidations in both lungs due to obstruction or stenosis on the bronchus, which did not respond to antibiotics, and proteinase-3-antineutrophil cytoplasmic autoantibody positivity, he was diagnosed with GPA. Positron emission tomography- computed tomography scan revealed no abnormal findings in the upper respiratory tract.</br> Interventions: </br> He was treated with prednisolone (PSL, 50 mg/d) and intravenous cyclophosphamide.</br> Outcomes: </br> His general and respiratory symptoms improved. However, 8 weeks after PSL treatment at 20 mg/d, he developed a relapse of vasculitis along with sinusitis and hypertrophic pachymeningitis. Hence, PSL treatment was resumed to 50 mg/d, and weekly administration of rituximab was initiated. Consequently, the symptoms gradually mitigated.</br> Lessons: </br> GPA with bronchial involvement is often intractable and requires careful follow-up, which should include upper respiratory tract and hypertrophic pachymeningitis assessment. No potential conflict of interest relevant to this article was reported.

Nature Research Acta Medica Okayama 2045-2322 10 1 2020 Risk of higher dose methotrexate for renal impairment in patients with rheumatoid arthritis 18715 EN Keigo Hayashi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken-Ei Sada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yosuke Asano Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Sumie Hiramatsu Asano Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuriko Yamamura Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Keiji Ohashi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Michiko Morishita Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Haruki Watanabe Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mariko Narazaki Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshinori Matsumoto Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jun Wada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Renal impairment is a major concern in patients taking high-dose methotrexate (MTX) for malignancy, but it has not been fully explored in rheumatoid arthritis (RA) patients taking low-dose MTX. This study aimed to elucidate the dose-dependent effects of MTX on the renal function of patients with RA. We retrospectively reviewed 502 consecutive RA patients who were prescribed MTX for >= 1 year at Okayama University Hospital between 2006 and 2018. The primary outcome was the change in estimated glomerular filtration rate (eGFR) over 1 year. The association between MTX dosage (<8, 8-12, and >= 12 mg/week) and the change in eGFR was evaluated using multiple linear regression analysis with adjustment for possible confounding factors including age, sex, disease duration, body weight, comorbidity, baseline eGFR, concomitant treatment, and disease activity. Mean patient age was 63 years; 394 (78%) were female. Median disease duration was 77 months, while mean MTX dosage was 8.6 mg/week. The last 1-year change of eGFR (mean +/- SD) in patients treated with MTX<8 (n=186), 8-12 (n=219),>= 12 mg/week (n=97) decreased by 0.2 +/- 7.3, 0.6 +/- 8.6, and 4.5 +/- 7.9 mL/min/1.73 m(2)/year, respectively (p<0.0001). After adjustment for the confounding factors, MTX >= 12 mg/week was still correlated with a decrease in 1-year eGFR (beta-coefficient:-2.5; 95% confidence interval,-4.3 to-0.6; p=0.0089) in contrast to MTX 8-12 mg/week. Careful monitoring of renal function is required in patients with MTX >= 12 mg/week over the course of RA treatment regardless of disease duration. No potential conflict of interest relevant to this article was reported.

BMC Acta Medica Okayama 1471-2369 21 1 2020 Association of explanatory histological findings and urinary protein and serum creatinine levels at renal biopsy in lupus nephritis: a cross-sectional study 208 EN Eri Katsuyama Department of Nephrology, Rheumatology, Endocrinology and Metabolism,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshia Miyawaki Department of Nephrology, Rheumatology, Endocrinology and Metabolism,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken-Ei Sada Department of Nephrology, Rheumatology, Endocrinology and Metabolism,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yosuke Asano Department of Nephrology, Rheumatology, Endocrinology and Metabolism,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Keigo Hayashi Department of Nephrology, Rheumatology, Endocrinology and Metabolism,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuriko Yamamura Department of Nephrology, Rheumatology, Endocrinology and Metabolism,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Sumie Hiramatsu-Asano Department of Nephrology, Rheumatology, Endocrinology and Metabolism,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Michiko Morishita Department of Nephrology, Rheumatology, Endocrinology and Metabolism,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Keiji Ohashi Department of Nephrology, Rheumatology, Endocrinology and Metabolism,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Haruki Watanabe Department of Nephrology, Rheumatology, Endocrinology and Metabolism,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takayuki Katsuyama Department of Nephrology, Rheumatology, Endocrinology and Metabolism,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mariko Narazaki Department of Nephrology, Rheumatology, Endocrinology and Metabolism,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshinori Matsumoto Department of Nephrology, Rheumatology, Endocrinology and Metabolism,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jun Wada Department of Nephrology, Rheumatology, Endocrinology and Metabolism,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Background</br> 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).</br> Methods</br> 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.</br> Results</br> 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).</br> Conclusion</br> 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. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 74 3 2020 Risk Factors for Chronic Damage Accumulation Across Different Onset Eras in Systemic Lupus Erythematosus: A Cross-sectional Analysis of a Lupus Registry of Nationwide Institutions (LUNA) 191 198 EN Keiji Ohashi Department of Nephrology, Rheumatology, Endocrinology, and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken-Ei Sada Department of Nephrology, Rheumatology, Endocrinology, and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yosuke Asano Department of Nephrology, Rheumatology, Endocrinology, and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Keigo Hayashi Department of Nephrology, Rheumatology, Endocrinology, and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuriko Yamamura Department of Nephrology, Rheumatology, Endocrinology, and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Sumie Hiramatsu Asano Department of Nephrology, Rheumatology, Endocrinology, and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshia Miyawaki Department of Nephrology, Rheumatology, Endocrinology, and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Michiko Morishita Department of Nephrology, Rheumatology, Endocrinology, and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Eri Katsuyama Department of Nephrology, Rheumatology, Endocrinology, and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Haruki Watanabe Department of Nephrology, Rheumatology, Endocrinology, and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Noriko Tatebe Department of Nephrology, Rheumatology, Endocrinology, and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mariko Narazaki Department of Nephrology, Rheumatology, Endocrinology, and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshinori Matsumoto Department of Nephrology, Rheumatology, Endocrinology, and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsue Sunahori-Watanabe Department of Nephrology, Rheumatology, Endocrinology, and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tomoko Kawabata Department of Nephrology, Rheumatology, Endocrinology, and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Nobuyuki Yajima Division of Rheumatology, Department of Medicine, Showa University School of Medicine Jun Wada Department of Nephrology, Rheumatology, Endocrinology, and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Original Article 10.18926/AMO/59949 Chronic damage accumulation affects not only mortality but also quality of life in patients with systemic lupus erythematosus (SLE). Risk factors for chronic damage were explored in SLE through different onset eras. Two hundred forty-five patients at Okayama University Hospital and Showa University Hospital were divided into three groups based on the onset era: a past-onset group (onset before 1995; n=83), middle-onset group (1996-2009; n=88), and recent-onset group (after 2010; n=74). The mean Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) score as an index of chronic damage was 1.93, 1.24, and 0.53 in the past-, middle-, and recent-onset groups, respectively. In the pastonset group, the total SDI score was significantly associated with glucocorticoid monotherapy by linear regression analysis (β-coefficient [β]=0.63; 95% confidence interval [CI], 0.21-1.05) and C-reactive protein levels (β=0.67; 95% CI, 0.27-1.07). In the middle-onset group, the total SDI score was significantly associated with the SLE Disease Activity Index at registration (β=0.09; 95% CI, 0.03-0.12). Reducing the accumulation of chronic damage in SLE patients might be possible with the concomitant use of immunosuppressants and tight control of disease activity. No potential conflict of interest relevant to this article was reported.

Nature Publishing Group Acta Medica Okayama 2045-2322 9 2019 Regulation of Cathepsin E gene expression by the transcription factor Kaiso in MRL/lpr mice derived CD4+T cells 3054 EN Sumie Hiramatsu Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsue S. Watanabe Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Sonia Zeggar Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yosuke Asano Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshia Miyawaki Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuriko Yamamura Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Eri Katsuyama Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takayuki Katsuyama Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Haruki Watanabe Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mariko Takano-Narazaki Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshinori Matsumoto Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tomoko Kawabata Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken-Ei Sada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jun Wada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences 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. No potential conflict of interest relevant to this article was reported.