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ObjectiveThis study aimed to understand the role of mammalian target of rapamycin (mTOR) in CD8+ cells in the pathogenicity of RA and the changes after treatment with biologic drugs.MethodsPeripheral blood mononuclear cells (PBMCs) were isolated from 17 healthy controls and 86 patients with RA. Phosphorylation of mTOR (p-mTOR) and its clinical relevance were evaluated. The role of mTOR in CD8+ cells was also examined in vitro.ResultsPatients with RA who had a moderate or high disease activity, were biologic-naïve, and were refractory to MTX were enrolled in this study. The p-mTOR levels in CD8+ cells were higher in patients with RA than in healthy controls, and they positively correlated with the disease activity in such patients. However, after one year of treatment with TNF inhibitors, the p-mTOR levels in CD8+ cells were suppressed and showed a positive correlation with the treatment response, which was not observed in the abatacept-treatment group. In vitro stimulation of CD8+ cells with anti-CD3 and anti-CD28 antibodies induced mTOR phosphorylation and increased the production of granzyme B, granulysin, TNF-α and IFN-γ but decreased the production of granzyme K. However, on treatment with TNF inhibitors, p-mTOR levels in CD8+ cells and granzyme B production decreased, while granzyme K production increased. The production of granulysin and IFN-γ was not affected by the TNF inhibitors.ConclusionThese results suggested that mTOR activation in CD8+ cells may be a novel evaluation marker for RA disease activity and a predictive marker of therapeutic response to TNF inhibitors.

In trials of systemic lupus erythematosus (SLE), the SLE Responder Index (SRI) is the most commonly used primary efficacy end point but has limited validation against long-term outcomes. We aimed to investigate associations of attainment of a modified version of the SRI (mSRI) with key clinical outcomes in SLE patients with up to 5 years of follow-up.We used data from a large multicenter, longitudinal SLE cohort in which patients received standard of care. The first visit with active disease (defined as SLE Disease Activity Index 2000 [SLEDAI-2K] score ≥6) was designated as baseline, and mSRI attainment (defined as a reduction in SLEDAI-2K ≥4 points with no worsening in physician global assessment ≥0.3 points) was determined at annual intervals from baseline up to 5 years. Associations between mSRI attainment and outcomes including disease activity, glucocorticoid dose, flare, damage accrual, Lupus Low Disease Activity State (LLDAS), and remission were studied.We included 2,060 patients, with a median baseline SLEDAI-2K score of 8. An mSRI response was attained by 56% of patients at 1 year, with similar responder rates seen at subsequent annual time points. Compared to nonresponders, mSRI responders had significantly lower disease activity and prednisolone dose and higher proportions of LLDAS and remission attainment at each year, and less damage accrual at years 2 and 3. Furthermore, mSRI responder status at 1 year predicted clinical benefit at subsequent years across most outcomes, including damage accrual (odds ratio [OR] range 0.58-0.69, P 0.05 for damage accrual ORs at all time points).In SLE patients with active disease receiving standard of care, mSRI attainment predicts favorable outcomes over long-term follow-up, supporting the clinical meaningfulness of SRI attainment as an SLE trial end point.

Objective Plasmablasts play important roles in autoimmune diseases, including systemic lupus erythematosus (SLE). Activation of mechanistic target of rapamycin complex 1 (mTORC1) is regulated by amino acid levels. In patients with SLE, mTORC1 is activated in B cells and modulates plasmablast differentiation. However, the detailed mechanisms of amino acid metabolism in plasmablast differentiation remain elusive. We undertook this study to evaluate the effects of methionine in human B cells. Methods Purified CD19+ cells from healthy donors (n = 21) or patients with SLE (n = 35) were cultured with Toll-like receptor 7/9 ligand, interferon-α (IFNα), and B cell receptor crosslinking, and we determined the types of amino acids that were important for plasmablast differentiation and amino acid metabolism. We also identified the transcriptional regulatory mechanisms induced by amino acid metabolism, and we assessed B cell metabolism and its relevance to SLE. Results The essential amino acid methionine strongly committed cells to plasmablast differentiation. In the presence of methionine, Syk and mTORC1 activation synergistically induced methyltransferase EZH2 expression. EZH2 induced H3K27me3 at BTB and CNC homolog 2 (Bach2) loci and suppressed Bach2 expression, leading to induction of B lymphocyte-induced maturation protein 1 and X-box binding protein 1 expression and plasmablast differentiation. CD19+ cells from patients with SLE overexpressed EZH2, which was correlated with disease activity and autoantibody production. Conclusion Our findings show that methionine activated signaling by controlling immunologic metabolism in B cells and played an important role in the differentiation of B cells into plasmablasts through epigenome modification of Bach2 by the methyltransferase EZH2.

Rheumatoid arthritis (RA) is associated with immune dysfunction. UBASH3A as a negative regulator of T cell receptors (TCRs) signaling is a susceptible factor in RA. The aim of this study was to determine the role of UBASH3A in RA pathogenesis, by assessing the role of super-enhancer (SE) in the control of UBASH3A expression in CD4UBASH3A mRNA and protein levels were quantified by PCR and western blotting, respectively. The cells were treated with a locked nucleic acid to inhibit enhancer RNA (eRNA) expression. Chromatin immunoprecipitation was used to identify the factors recruited to UBASH3A loci displaying SE architecture. CD4UBASH3A was extracted as a RA susceptibility gene associated with SNPs in the SEs that are highly expressed in CD4In RA, transcription of UBASH3A is suppressed via epigenetic regulation of SE in CD4

Background Rheumatoid arthritis (RA) is associated with immune dysfunction. UBASH3A as a negative regulator of T cell receptors (TCRs) signaling is a susceptible factor in RA. The aim of this study was to determine the role of UBASH3A in RA pathogenesis, by assessing the role of super-enhancer (SE) in the control of UBASH3A expression in CD4+ T cells and the contribution of the latter in proinflammatory cytokine production in patients with RA. Methods UBASH3A mRNA and protein levels were quantified by PCR and western blotting, respectively. The cells were treated with a locked nucleic acid to inhibit enhancer RNA (eRNA) expression. Chromatin immunoprecipitation was used to identify the factors recruited to UBASH3A loci displaying SE architecture. CD4+ T cells were transfected with UBASH3A plasmids, and cytokine levels were measured by a cytometric bead array. Results UBASH3A was extracted as a RA susceptibility gene associated with SNPs in the SEs that are highly expressed in CD4+ T cells by in silico screening. UBASH3A mRNA and protein expression levels were lower in CD4+ T cells of RA patients than in the control. eRNA_1 and eRNA_3 knockdown reduced UBASH3A mRNA levels. RA patients exhibited accumulation of BTB and CNC homology 2 (BACH2), the silencing transcription factor, at the UBASH3A loci in CD4+ T cells, but not the SE-defining factor, mediator complex subunit 1 (MED1)/bromodomain 4 (BRD4). However, opposite changes were observed in the control. Stimulation of TCRs expressed on CD4+ T cells of RA patients resulted in interleukin (IL)-6 production, while UBASH3A over-expression significantly inhibited the production. Conclusions In RA, transcription of UBASH3A is suppressed via epigenetic regulation of SE in CD4+ T cells. Low UBASH3A levels result in excessive TCR signal activation with subsequent enhancement of IL-6 production.

Objectives To clarify the effectiveness and safety of induction therapy with mycophenolate mofetil (MMF) in patients with lupus nephritis (LN). Methods Patients with LN administered MMF (n = 35) or intravenous cyclophosphamide pulse therapy (IVCY) (n = 25) plus high-dose corticosteroids between July 2015 and June 2020 were included. MMF was increased from 2 to 3 g/day, with no adverse events (AEs). The primary endpoint was the 6 month renal remission rate. Secondary endpoints were retention rate and AEs. Results There were no significant differences in age, sex, disease duration, renal histological type, SLE disease activity index, and urine protein creatinine ratio between the two groups. Twenty-six patients (74%) continued with MMF therapy, whereas 12 (48%) completed six IVCY courses. The retention rate was significantly higher in the MMF than in the IVCY group (p = 0.048). Twenty-four and 14 patients in MMF and IVCY groups, respectively, achieved renal remission with insignificant differences. Grade 3 or higher AEs were observed in 8 and 14 patients in the MMF and IVCY groups, respectively (p = 0.014). Conclusions The efficacy of high-dose MMF was comparable to that of IVCY in Japanese patients with proliferative LN, with fewer AEs and a higher retention rate than IVCY, suggesting the high tolerability of MMF.

ObjectivesB cells play an important pathological role in RA. In this study, we investigated the role of metabolic regulator mTOR in B cells and its relevance to the pathology of RA.MethodsPeripheral blood mononuclear cells were isolated from 31 normal subjects and 86 RA patients and the gated B cells were assessed for mTOR phosphorylation and chemokine receptor expression. In vitro studies on peripheral blood B cells isolated from the control and RA patients investigated the molecular mechanisms.ResultsHigher concentrations of CXCL10 (CXCR3 ligands) and lower percentages of CXCR3+ memory B cells were present in the peripheral blood of RA patients relative to the control. RA patients with high CXCL10 concentrations had smaller percentage of CXCR3+ memory B cells and high disease activity. One-year treatment with TNF inhibitors increased the percentage of CXCR3+ memory B cells and reduced serum CXCL10 concentrations. mTOR phosphorylation in B cells was further enhanced in RA patients, compared with the control, and was selectively enhanced in CXCR3+ memory B cells. mTOR phosphorylation in CXCR3+ memory B cells correlated with disease activity. In vitro, mTOR phosphorylation in B cells enhanced IL-6 production and increased RANKL expression.ConclusionmTOR activation in CXCR3+ memory B cells of RA patients is associated with disease activity, mediated through IL-6 production and RANKL expression. The obtained results also suggest that TNF inhibitors mediate an impact on the association between CXCL10 and mTOR activated CXCR3+ memory B cells.

We report the case of a 65-year-old woman who developed bullous erythema on her face in X-4. The test result for anti-Dsg-1 antibody was positive, and acantholytic blisters were found on skin biops...

BACKGROUND Systemic lupus erythematosus (SLE) is related to vasculitis, which causes brain infarctions; however, the pathology of large cerebral vessels has not been fully established. PURPOSE To demonstrate the prevalence of vessel wall lesions (VWLs) in SLE patients using 3D vessel wall imaging and to assess the relationship between VWLs and brain infarctions. STUDY TYPE Retrospective. SUBJECTS Sixty SLE patients and 50 healthy subjects (HS). FIELD STRENGTH/SEQUENCE Each subject underwent 3T MRI, which included 3D FSE PDWI (CUBE). ASSESSMENT For each of the 33 segments of the intracranial artery (internal carotid artery ∼ M3 segment of middle cerebral artery [MCA]), the VWLs were scored as either positive or negative, and the VWL score was calculated as the sum of the segments with VWLs. We also evaluated brain lesions on conventional MRI. STATISTICAL TESTS We used logistic regression analyses to determine the clinical (serological test and cardiovascular risk factors) and imaging characteristics associated with infarctions in SLE patients. RESULTS For the peripheral vessels such as MCA, VWLs were more common for SLE patients than for HS (43.3% versus 16.7% in M1 segment, 60.4% versus 16.7% in M2 segment, both P

Background T helper 1 (Th1) cells play an important role in Systemic Lupus Erythematosus (SLE). However, which abnormalities generated in Th1 cells may be related to the pathogenesis of SLE remains elusive. “Immunometabolism” has recently attracted much attention. We previously reported that both IFN-γ and T-bet positively regulated aerobic glycolysis, leading to activation of Th1 cells in mice (REF1). This suggests a potentially important role for metabolic reprograming in human Th1 cells and the pathogenesis of SLE which requires further investigation. Objectives In this study, we assessed the abnormality of metabolism in Th1 cells in patients with SLE. In addition, we investigated which abnormalities of Th1 cells are generated via metabolic reprograming in vitro. Methods Peripheral blood mononuclear cells (PBMCs) were obtained from 31 age-matched healthy donors (HDs) and 60 patients with SLE. Th1- and metabolism-related markers in CD4+ T cells were measured by flow cytometry. In addition, the correlation of these markers with clinical characteristics was investigated. Next, CD4+CD45RA- cells were purified from peripheral of HDs, and the effect of mTORC1 inhibitor Rapamycin (Rapa) or glycolysis inhibitor 2DG on characteristic changes in Th1 cells were assessed in vitro. Results Baseline characteristics of patients with SLE were males: females=5:55, age 41.1 years, disease duration 142.3 months, SLEDAI 11.5 and BILAG 12.9 at the timing of admission due to exacerbation of SLE. Activated effector memory CD4+T-bethi cells in patients with SLE were higher than HCs. The CD4+T-bethi cells had high potential for IFN-γ production. mTORC1 acts as a regulator of cell growth through the phosphorylation of substrates that potentiate anabolic processes such as aerobic glycolysis. The CD4+T-bethi cells highly expressed p-mTORC1, and this was closely related to treatment-resistance, but not disease activity and autoantibodies such as anti ds-DNA Abs (Treatment resistance was defined as refractory to >3 kinds of immunosupressants and/or 2> re-increase to high dose corticosteroid). Therefore, we examined the effect of Rapa or 2DG to such memory mTORC1+T-bet+IFNγ+CD4+ cells in vitro. When CD45RA-CD4+ cells were isolated from peripheral blood of HDs and stimulated with anti-CD3/CD28 Abs, T-bet expression and IFN-γ production as well as p-mTOC1 expression and glycolysis were induced. Interestingly, 2DG, but not Rapa, suppressed IFN-γ production and, in contrast, enhanced IL-2 production. Therefore, we hypothesized that 2DG induced Th1-Treg cells, reported as one of Treg cell subsets (REF2). 2DG induced FoxP3hiT-bet+IFN-γ- (Th1-Treg like) cells and suppressed FoxP3-T-bet+IFN-γ+ (Th1 like) cells. Meanwhile, Rapa induced FoxP3intT-bet+IFN-γ+ (non-Treg like) cells and did not affect to FoxP3-T-bet+IFN-γ+ (Th1 like) cells. Finally, we examined the involvement of Th1-Treg cells to the pathogenesis of SLE. CD45RA-FoxP3intIFN-γ+ (non-Treg) cells as well as T-bethi (Th1 like) cells were increased, whereas CD45RA-FoxP3hiCXCR3+T-bethi (Th1-Treg) cells were decreased in SLE. Conclusion These results indicate that activated effector memory Th1 cells were increased while memory Th1-Treg cells were decreased in patients with SLE. Importantly, metabolic modulators redressing the imbalance of helper T subsets have potential as a new therapeutic strategy. References [1] Iwata S, et al. Immunity. 2017;46:983-91. [2] Levine AG, et al. Nature. 2017;546:421-25. Disclosure of Interests Shigeru Iwata: None declared, Mingzeng Zhang: None declared, Maiko Hajime: None declared, Naoaki Ohkubo: None declared, Hiroko Miyata: None declared, Yasuyuki Todoroki: None declared, Shingo Nakayamada Grant/research support from: Mitsubishi-Tanabe, Takeda, Novartis and MSD, Speakers bureau: Bristol-Myers, Sanofi, Abbvie, Eisai, Eli Lilly, Chugai, Asahi-kasei and Pfizer, Yoshiya Tanaka Grant/research support from: Abbvie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, MSD, Ono, Taisho-Toyama, Takeda, Speakers bureau: Abbvie, Asahi-kasei, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eli Lilly, Eisai, Glaxo-Smithkline, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer Japan Inc, Sanofi, Takeda, UCB, YL Biologics

Background: B cells play an important role in systemic lupus erythematosus (SLE). Several research protocols have focused in recent years on the topic of immunometabolism. Activation of immunocompetent cells depends on rapid synthesis of cell structure components and biomolecules, which requires enormous amounts of energy, nucleic acids and lipids. Amino acids are important ingredients of many metabolic processes. However, the role of amino acids in plasmablast differentiation and their relevance to the pathogenesis of SLE remain elusive. Objectives: To determine the role of essential amino acids in human B cell differentiation and relevance to the pathogenesis of SLE. Methods: In the in vitro arm of the study, purified CD19+ B cells from healthy donors were cultured with TLR7/9 ligand (LOX or CpG), IFN-α and B cell receptor (BCR) cross-linking, in the presence or absence of amino acids. We determined 1) the types of amino acids that are important for PB differentiation, 2) the amino acid transporters that are important for PB differentiation, 3) the main signaling pathway(s) involved in the presence of amino acids, 4) the transcriptional factors used in the presence of amino acids. In the clinical arm of the study, peripheral blood mononuclear cells (PBMCs) were obtained from 24 patients with RA, 35 patients with SLE, and 28 age-matched healthy controls, and subjected to flow cytometric analysis to determine the expression of amino acids-related markers. Results: 1) Stimulation with the combination of BCR, IFN-α and TLR7/9 ligand induced PB differentiation accompanied by uptake of amino acids. PB differentiation was abrogated in the absence of essential amino acid methionine, and to a lesser extent leucine, but not in non-essential amino acid cystine. 2) LAT1 and CD98 are known amino acid transporters. Stimulation with BCR, IFN-α and TLR7/9 ligand induced CD98 expression but suppressed LAT1 expression. CD98 expression was higher in CD27hiCD38hi PB than in CD27-CD38- non-PB. 3) Previous studies reported that amino acids were perceived by the sensor, leading to mTORC1 phosphorylation. However, the mechanism by which amino acids activate other intracellular signaling pathways in B cells remains elusive. We found that methionine facilitated both the BCR and mTORC1 signals. In addition, the two signals synergistically induced EZH2 expression, which is well known as a transcriptional factor for histone modification via induction of H3K27me3, in the presence of methionine. 4) Methionine induced EZH2 expression, leading to suppression of BACH2, induction of BLIMP1, XBP1 and PB differentiation. These results indicate that EZH2 is a critical factor for PB differentiation in the presence of methionine. Assessment of the expression of amino acid transporters CD98, LAT1 and EZH2 in B cells in RA and SLE patients showed overexpression of CD98 and EZH2, but not LAT1, in SLE, compared with RA and control. In SLE patients, EZH2 expression level correlated with that of CD98 in B cells. EZH2 expression also correlated with ESR and disease activity scores, such as of SLEDAI and BILAG, in SLE patients. Conclusion: The results indicate that essential amino acid methionine plays an important role in PB differentiation through the CD98-EZH2-axis. The pathological process of SLE seems to involve essential amino acids and their metabolic/activation pathways throughout the process of PB differentiation. Disclosure of Interests: Mingzeng Zhang: None declared, Shigeru Iwata: None declared, Maiko Hajime: None declared, Naoaki Ohkubo: None declared, Yasuyuki Todoroki: None declared, Hiroko Miyata: None declared, Shingo Nakayamada Grant/research support from: Mitsubishi-Tanabe, Takeda, Novartis and MSD, Speakers bureau: Bristol-Myers, Sanofi, Abbvie, Eisai, Eli Lilly, Chugai, Asahi-kasei and Pfizer, Yamagata Kaoru: None declared, Yoshiya Tanaka Grant/research support from: Abbvie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, MSD, Ono, Taisho-Toyama, Takeda, Speakers bureau: Abbvie, Asahi-kasei, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eli Lilly, Eisai, Glaxo-Smithkline, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer Japan Inc, Sanofi, Takeda, UCB, YL Biologics

Background:Systemic lupus erythematosus (SLE) is a complex polygenic autoimmune disease characterized by immune-system aberrations. Among several types of immune cells, T follicular helper (Tfh) cells promote autoantibody production, whereas T follicular regulatory (Tfr) cells suppress Tfh-mediated antibody responses.(1)Objectives:To identify the characteristics of Tfr cells and to elucidate the mechanisms of conversion of Tfh cells to Tfr cells, we probed the phenotype of T helper cells in patients with SLE and underlying epigenetic modifications by cytokine-induced signal transducer and activators of transcription (STAT) family factors.Methods:Peripheral blood mononuclear cells from SLE patients (n=44) and healthy donors (HD; n=26) were analyzed by flow cytometry. Memory Tfh cells were sorted and cultured under stimulation with T cell receptor and various cytokines. Expression of characteristic markers and phosphorylation of STATs (p-STATs) were analyzed by flow cytometry and quantitation PCR. Histone modifications were evaluated by chromatin immunoprecipitation.Results:The proportion of CXCR5+FoxP3+Tfr cells in CD4+T cells tended to increase (2.1% vs 1.7%, p=0.17); however, that of CD4+CD45RA-FoxP3hiactivated Tfr cells in Tfr cells was decreased (4.8% vs 7.1%, p+CD45RA-FoxP3lownon-suppressive Tfr cells was increased (50.1% vs 38.2%, phiactivated Tfh cells was significantly higher in SLE compared to HD (15.7% vs 5.9%, p+Bcl6+Foxp3hipSTAT3+pSTAT5+cells. The loci ofFOXP3at STAT binding sites were marked by bivalent histone modifications. After IL-2 stimulation, STAT5 directly bound on FOXP3 gene loci accompanied by suppressing H3K27me3. Finally, we found that serum level of IL-2 was decreased in SLE and that stimulation with IL-2 suppressed the generation of CD38+CD27+B cells by ex vivo coculture assay using Tfh cells and B cells isolated from human blood.Conclusion:Our findings indicated that the regulatory function of Tfr cells is impaired due to the low ability of IL-2 production and that IL-2 restores the function of Tfr cells through conversion of Tfh cells to Tfr cells in SLE. Thus, the reinstatement of the balance between Tfh and Tfr cells will provide important therapeutic approaches for SLE.References:[1]Deng J, Wei Y, Fonseca VR, et al. T follicular helper cells and T follicular regulatory cells in rheumatic diseases. Nat Rev Rheumatol. 2019; 15 (8): 475-90.Disclosure of Interests: :He Hao: None declared, Shingo Nakayamada Grant/research support from: Mitsubishi-Tanabe, Takeda, Novartis and MSD, Speakers bureau: Bristol-Myers, Sanofi, Abbvie, Eisai, Eli Lilly, Chugai, Asahi-kasei and Pfizer, Yamagata Kaoru: None declared, Naoaki Ohkubo: None declared, Shigeru Iwata: None declared, Yoshiya Tanaka Grant/research support from: Asahi-kasei, Astellas, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Pfizer, and Ono, Consultant of: Abbvie, Astellas, Bristol-Myers Squibb, Eli Lilly, Pfizer, Speakers bureau: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Sanofi, UCB, and Teijin

Objective We examined the efficacy and safety of rituximab in patients with refractory systemic lupus erythematosus (SLE). Methods The study enrolled 63 SLE patients who were treated with rituximab between 2002 and 2015. The participants underwent a battery of tests before treatment and at one year. Treatment ranged from two to four times at 500 or 1000 mg. Results Baseline characteristics were males:females = 6:57, age 33.9 years, and disease duration 87.2 months. The primary endpoint: The rate of major clinical response (MCR) was 60% while the partial clinical response (PCR) was 25%. Thirty of 36 (83%) patients with lupus nephritis (WHO II: 2, III: 5, IV: 22, V: 4, IV+V: 2, not assessed: 1) and 22 of 24 patients (92%) with neuropsychiatric SLE, who could be followed at one year, showed changes from BILAG A or B score to C or D score at one year. Multivariate analysis identified high anti-dsDNA antibody and shorter disease duration as significant determinants of MCR at one year. Repeat examination was conducted at five years. Primary failure was recorded in 8.8% and secondary failure in 32.4% (time to relapse: 24.4 months). Rituximab was well tolerated although 65 adverse events, mostly infections, were recorded within one year. Conclusion Rituximab is potentially efficacious for the treatment of patients with refractory SLE.

Systemic lupus erythematosus (SLE) is related to vasculitis, which causes brain infarctions; however, the pathology of large cerebral vessels has not been fully established.To demonstrate the prevalence of vessel wall lesions (VWLs) in SLE patients using 3D vessel wall imaging and to assess the relationship between VWLs and brain infarctions.Retrospective.Sixty SLE patients and 50 healthy subjects (HS).Each subject underwent 3T MRI, which included 3D FSE PDWI (CUBE).For each of the 33 segments of the intracranial artery (internal carotid artery ∼ M3 segment of middle cerebral artery [MCA]), the VWLs were scored as either positive or negative, and the VWL score was calculated as the sum of the segments with VWLs. We also evaluated brain lesions on conventional MRI.We used logistic regression analyses to determine the clinical (serological test and cardiovascular risk factors) and imaging characteristics associated with infarctions in SLE patients.For the peripheral vessels such as MCA, VWLs were more common for SLE patients than for HS (43.3% versus 16.7% in M1 segment, 60.4% versus 16.7% in M2 segment, both P 0.01). There were 21 infarctions in 13 patients (21.7%), and the median VWL score was larger in the patients with infarctions than in those without (13 versus 6, P 0.01). Multivariate logistic regression analyses revealed a high VWL score ( ≥ 9) to be the only factor independently associated with the presence of infarctions (odds ratio: 10.1, 95% confidence interval: 1.01-101; P 0.049).We demonstrated a substantially high prevalence of VWLs among SLE patients, which were associated with brain infarctions.3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1237-1246.

Background and aims B cells play a crucial role in pathogenesis of Systemic Lupus Erythematosus(SLE). We examined the efficacy of B cell depletion therapy rituximab for refractory patients with SLE. Methods 63 eligible study subjects since 2002 until 2015 were men and women, who met the American College of Rheumatology criteria in 1987 or SLICC2012 for the classification of SLE. The protocols were approved by the Institutional Review Board of our university. Treatment protocol: 2 or 4 weekly doses of 500 mg/body, 2 biweekly doses of 1000 mg/body or 4 weekly doses of 1000 mg/body. Results Baseline characteristics; gender M:F=6:57, age 33.9 years, disease duration 87.2 months, organ failure NPSLE:35, lupus nephritis:46, treated with IVCY 34/63. The 60/63 patients were trailable at 1 year. Primary endpoint; disease activity scores were significantly improved (SLEDAI 17.3→3.0, BAILAG 17.8→2.2; LOCF). The achievement ratio of major clinical response (MCR) defined as no BILAG A and/or B score was 61.7%. Secondary endpoint; dose of corticosteroid was decreased from 43.2 to 8.4 mg/day. Nephritis score originally designed (total 10 points; protein 3, occult blood 3, cast 4) was decreased (3(before)→2.3 (1month)→0.8 (1year)). The 37/50 patients were trailable at 5 years. Primary failure: 3 (8%), secondary failure (flare) : 12 (32.8%, duration: 23.8 months), MCR: 18 (48.6%), corticosteroid discontinued: 5 among 37 patients. Conclusions Rituximab showed short-term and long-term efficacy in refractory patients with SLE, although some of patients had a relapse. Rituximab could be considered as a therapeutic strategy for refractory patients with SLE.

Background and Aims CD4 + T cells play a crucial role in pathological process of Systemic Lupus Erythematosus (SLE). Recently, we found that T-bet is an important factor for shift to glycolysis in activated CD4 + T cells in vitro . In this study, we examined the mechanism by which T-bet in CD4 + T cells involved in pathogenesis of SLE. Methods Peripheral blood mononuclear cells were obtained from 19 healthy controls (HCs), 30 patients with bio-naive active RA and 60 patients with SLE. The expression of CXCR3, T-bet, mTORC1 phosphorylation and IFN-γ production in CD4 + T cells were measured by flow cytometry, and assessed the association with clinical characteristics. Results We found that the ratio of CD28 - CXCR3 int T-bet hi cells in patients with SLE was significantly higher compared to HCs. CD4 + CD28 - CXCR3 int T-bet hi cells mainly consisted of CD45RA - CCR7 - effector memory cells and were significantly activated with pronounced IFN-γ production. Interestingly, the ratio of CD4 + CD28 - CXCR3 int T-bet hi cells was significantly correlated with the number of immunosuppressants previously used for the SLE patients, that is treatment-resistant. Phosphorylation of mTORC1, which is important for shift to glycolysis, in CD4 + T cells from patients with SLE was significantly increased compared to HCs. T-bet expression was significantly correlated with mTOC1 phosphorylation and IFN-γ production in CD4 + T cells from patients with SLE. Conclusions These results indicated that CD4 + CD28 - CXCR3 int T-bet hi cells might be related to refractory to established therapies in patients with SLE. In addition, these cells are constitutively activated accompanied with shift to glycolysis through IFN-γ-mTORC1-T-bet pathway, which is a potential target for patients with SLE.

A 64-year-old man has revealed dry cough and severe pain of ear, nose and throat for several weeks. After visiting clinics and hospitals, he was introduced to our hospital and was diagnosed as relapsing polychondritis (RP) based on McAdam's criteria. The involvement in auricular, nasal and tracheal cartilage was clearly shown by fusion images of gallium-67 on single photon emission computed tomography and computed tomography (SPECT/CT) (A, B). High-dose glucocorticoid (GC) therapy markedly improved relevant signs, symptoms and inflammatory reactions as well as gallium uptake in cartilage detected by gallium-SPECT/CT (C). This article is protected by copyright. All rights reserved.

One of the critical issues in MTCMOS design is how to estimate a circuit delay quickly. In this paper, we propose a delay modeling and static timing analysis (STA) methodology targeting at MTCMOS circuits. In the proposed method, we prepare a delay look-up table (LUT) consisting of the input slew, the output load capacitance, the virtual ground length, and a power-switch size. Using this LUT, we compute a circuit delay for each logic cell by applying the linear interpolation. Experimental results show that the proposed methodology enables to estimate the critical path delay in a good accuracy.