Population characteristics and diagnosis rate of chronic kidney disease by eGFR and proteinuria in Japanese clinical practice: an observational database study.

Chronic kidney disease (CKD) guidelines recommend early identification and intervention to delay the progression of CKD. The Kidney Disease: Improving Global Outcomes (KDIGO) heatmap is widely used for risk evaluation in CKD management; however, real-world evidence on clinical characteristics based on the KDIGO heatmap remains limited worldwide including Japan. In order to understand the management of CKD including its diagnostic rates in a Japanese clinical setting on the basis of KDIGO heatmap, we utilized a medical record database that contains estimated glomerular filtration rate (eGFR) and urine protein data. Adult individuals (≥ 18 years) with two eGFR results of < 90 mL/min/1.73 m2, 90-360 days apart, were included. Approximately half of patients (452,996/788,059) had proteinuria test results and 6.9% (54,073) had quantitative results. CKD diagnosis rate in patients without proteinuria data was 5.9%, with a lower rate (2.9%) in stage G2; the corresponding rates with quantitative test results were 43.5% and 31.3%, respectively. The most frequent comorbidities were hypertension, diabetes, and cardiovascular disease, and their prevalence increased as the eGFR and proteinuria stages progressed. This study revealed a low rate of proteinuria assessment, especially using quantitative methods, and diagnosis in individuals with suspected CKD. With emerging treatment options to prevent CKD progression and complication onset, there is a need for early evaluation and diagnosis of CKD.

Persistent Risk of Developing Autoimmune Diseases Associated With COVID-19: An Observational Study Using an Electronic Medical Record Database in Japan.

OBJECTIVE: This study aimed to investigate the risk of developing autoimmune diseases associated with coronavirus disease 2019 (COVID-19) in Japan, including long-term risks and risks specific to different variants of concern. METHODS: This observational study used an electronic medical record database in Japan. The COVID-19 group is composed of patients diagnosed with COVID-19, whereas the non-COVID-19 group had data sampled from the database. The outcomes of interest encompassed several autoimmune diseases, including rheumatoid arthritis, systemic sclerosis, and immunoglobulin G4-related disease, as well as a composite of these diseases (any autoimmune disease). We examined the relative risk of autoimmune diseases using standardized mortality ratio weighting and the Cox proportional hazards model. Subgroup analyses based on epidemic variants were performed. In addition, short- and long-term risks were investigated using piecewise constant hazard models. RESULTS: A total of 90,855 COVID-19 and 459,827 non-COVID-19 patients were included between January 16, 2020, and December 31, 2022. The relative risk of any autoimmune disease was 2.32 (95% confidence interval, 2.08-2.60). All the investigated outcomes showed a significant risk associated with COVID-19. Several autoimmune diseases exhibit a risk associated with COVID-19 in the short to long term, and the long-term risk is substantial for systemic sclerosis and immunoglobulin G4-related disease. The variant-specific risk varied across outcomes. CONCLUSIONS: COVID-19 is associated with an increased risk of developing autoimmune diseases in the Japanese population, and this effect persists for a long time. This study provides insights into the association between viral infections and autoimmunity.

Glucocorticoid treatment and clinical outcomes in patients with polymyalgia rheumatica: A cohort study using routinely collected health data.

OBJECTIVE: We aimed to describe the following in patients with polymyalgia rheumatica (PMR): (1) real-world glucocorticoid (GC) therapy, (2) improvement in inflammatory parameters associated with disease activity (C-reactive protein [CRP] level and erythrocyte sedimentation rate [ESR]), and (3) incidence of GC-related adverse events (AEs). METHODS: A cohort study was conducted using a Japanese electronic medical records database. We included newly diagnosed PMR patients aged≥50years with baseline CRP levels≥10mg/L and/or ESR>30mm/h and an initial GC dose of≥5mg/day. The outcomes were GC dose, inflammatory parameters, and GC-related AEs. RESULTS: A total of 373 PMR patients (mean age, 77.3 years) were analyzed. The median initial GC dose was 15.0mg/day, which gradually decreased to 3.5mg/day by week 52. The median cumulative GC dose at week 52 was 2455.0mg. The median CRP level on day 0 was 64.3mg/L, which decreased during weeks 4-52 (1.4-3.2mg/L). At week 52, 39.0% of patients had a CRP level>3.0mg/L. The cumulative incidence of GC-related AEs at week 52 was 49.0% for osteoporosis, 30.2% for diabetes, 14.9% for hypertension, 12.2% for peptic ulcer, 11.3% for dyslipidemia, 2.9% for glaucoma, and 4.3% for serious infection. The incidence of osteoporosis and diabetes increased with the GC dose. CONCLUSION: The incidence of GC-related AEs was associated with the GC dose in PMR patients. Further research is required to identify treatment strategies that can effectively control PMR disease activity while minimizing GC use.

Treatment of Chronic Constipation using Elobixibat in a Real-World Setting: A Retrospective Cohort Study using an Electronic Medical Records Database in Japan.

Background: Chronic constipation is a common condition affecting people of all ages; therefore, the socioeconomic burden of chronic constipation is nonnegligible. Elobixibat (ELO), an ileal bail acid transport inhibitor, was launched in Japan in 2018. However, evidence of its use in diverse populations is limited. Objectives: This study aimed to evaluate the prescription of ELO, risk factors associated with ELO discontinuation, and the continuation of stimulants or saline laxatives during ELO treatment in a real-world setting using an extensive electronic medical records database that primarily includes data from acute-care hospitals. Methods: Data of patients prescribed for ELO from April 1, 2018, to March 31, 2022, were extracted from the database. The discontinuation of ELO and stimulant or saline laxatives during ELO treatment was evaluated using the Kaplan-Meier method. The Cox proportional hazards model evaluated risk factors associated with laxative discontinuation. Results: In total, 11,062 patients were evaluated. The rate of ELO discontinuation within 360 days of initiation was 78.7%. Hospitalized at the ELO initiation, stage 5 chronic kidney disease, and diagnosis of constipation by departments of obstetrics and gynecology or by departments of malignant neoplasm were identified as risk factors for discontinuation. Diagnosis of constipation, diabetes mellitus, Parkinson's disease, and previous laxative treatment was associated with a lower risk of ELO discontinuation. The prescription rate of stimulants and saline laxatives markedly decreased after ELO initiation; furthermore, nearly half of patients who were continuously prescribed ELO discontinued these laxatives within 360 days. Conclusions: The discontinuation of ELO was associated with various factors and using ELO may be beneficial in the withdrawal of concurrent stimulants and saline laxatives. These findings may help effectively manage chronic constipation.

Real-World Hepatic Safety of Oral Acetaminophen Versus Loxoprofen/Celecoxib: Using a Nationwide Electronic Medical Record Database.

The aim of this study was to investigate the incidence of liver injury associated with acetaminophen compared with 2 commonly prescribed non-steroidal anti-inflammatory drugs, loxoprofen and celecoxib, over 1-year period. This study used an electronic medical record database obtained from 219 medical institutions in Japan. Eligible patients were individuals with an initial prescription of oral acetaminophen, loxoprofen, or celecoxib prescribed for ≥28 days of treatment between January 2015 and December 2019. The primary outcome was the incidence rate of liver injury, defined as a diagnosis of liver disease and an elevated alanine aminotransferase (ALT) level (>3 times the upper limit of normal). The primary hypothesis was that acetaminophen would be non-inferior to loxoprofen or celecoxib with regard to the incidence of liver injury, with a non-inferiority margin of 1.39. As a result, a total of 83,976 patients were eligible for inclusion in this study. The numbers of events per 100 person years for the primary outcome were 0.64, 0.52, and 0.41 for acetaminophen, loxoprofen, and celecoxib, respectively; these differences did not meet the non-inferiority margin. The results for the 2 secondary outcomes for acetaminophen, loxoprofen, and celecoxib were incidence rates (events per 100 person years) of a diagnosis of liver disease of 1.51, 1.38, and 1.11, respectively, and incidence rates of elevated ALT of 9.69, 7.75, and 7.90, respectively; 3 of 4 comparison group differences did meet the non-inferiority margin. In conclusion, the non-inferiority of acetaminophen to loxoprofen and celecoxib in terms of the risk of liver injury in clinical practice was inconclusive in this study.

Descriptive epidemiology of COVID-19 in Japan 2020: insights from a multihospital database.

BACKGROUND: Epidemiological data are essential for developing strategies against the current coronavirus disease 2019 (COVID-19) pandemic. Data on COVID-19 epidemiology in Japan are limited owing to a focus on specific regions and patient groups, particularly in the early phase of the pandemic. METHODS: We investigated COVID-19 epidemiology in Japan in 2020 using a large nationwide multihospital database containing insurance claim records and medical records. Inclusion criteria were inpatient and outpatient referrals for COVID-19 in 2020. We analyzed demographic data, comorbidities, drug use, severe COVID-19 risk, and clinical course of hospitalized patients (including death). RESULTS: We identified 11,868 COVID-19 cases from 56 institutions: 6,440 outpatients and 5,428 inpatients. Of the patients, 53.2% had comorbid conditions, the most common of which was tumor (22.1%), and 56.4% were classed as having a high risk of COVID-19. Pharmacological management patterns were generally consistent between the first and second half of 2020, except for glucocorticoid use. The use of unauthorized medications (hydroxychloroquine, ivermectin, and favipiravir) was infrequent. For hospitalized patients, the median length of stay was 10 days, and 2.4% of patients were admitted to intensive care units. Post-COVID-19 all-cause mortality, all-cause 30-day mortality, and in-hospital deaths were recorded for 7.9%, 5.4%, and 4.6% of patients, respectively. Patients with high-risk conditions had a lower survival probability. CONCLUSIONS: This descriptive study of COVID-19 in 2020 identified differences in care across outpatient and inpatient settings and changes in care delivery as the pandemic progressed. These findings could inform strategies for future infectious disease pandemics.

TNFR2 Signaling Enhances Suppressive Abilities of Human Circulating T Follicular Regulatory Cells.

T follicular regulatory (Tfr) cells are a subset of CD4+ T cells that express CXCR5 and migrate into germinal centers (GCs). They regulate GC reactions by communicating with T follicular helper (Tfh) and B cells. TNF inhibitors are used in inflammatory diseases; however, the generation of autoantibodies or anti-drug Abs sometimes causes problems. Because TNFR2 signaling is important for suppressive functions of regulatory T cells, we investigated the role of TNFR2 on human Tfr cells. Tfr cells stimulated with MR2-1 (an anti-TNFR2 agonistic Ab) were analyzed for cell proliferation, Foxp3 expression, and surface molecules. Tfh/B cell proliferation, IgM production, and differentiation in cocultures with MR2-1-stimulated Tfr cells were examined. Tfr cells express a high level of TNFR2. MR2-1 stimulation altered the gene expression profile of Tfr cells. Cell proliferation and Foxp3 expression of Tfr cells were enhanced by MR2-1. MR2-1-stimulated Tfr cells expressed ICOS and Programmed cell death protein 1 and significantly suppressed Tfh/B cell proliferation, IgM production, and B cell differentiation. TNFR2-stimulated Tfr cells retained the migration function according to the CXCL13 gradient. In conclusion, we showed that TNFR2-stiumulated Tfr cells can regulate Tfh and B cells. Aberrant antibody production during TNF inhibitor treatment might be, at least in part, associated with TNFR2 signaling inhibition in Tfr cells. In addition, expansion and maturation of Tfr cells via TNFR2 stimulation in vitro may be useful for a cell-based therapy in inflammatory and autoimmune diseases to control GC reactions.

Activation of caspase-1 is mediated by stimulation of interferon genes and NLR family pyrin domain containing 3 in monocytes of active systemic lupus erythematosus.

OBJECTIVES: Emerging evidence has shown the importance of inflammasome activation in the progression of autoimmune diseases. In this study, we aimed to identify the main cell types activating inflammasome in autoimmune diseases and to clarify the intracellular pathway of inflammasome activation in systemic lupus erythematosus (SLE). METHODS: Active caspase-1 in each subset of human peripheral blood cells from healthy controls (n=18), SLE (n=51), and other rheumatic diseases (n=36) were fluorescently probed with FLICA™-caspase-1 followed by flow cytometric analysis. The correlation of caspase-1 activation in monocytes and clinical parameters in SLE patients were evaluated. In-vitro experiments were performed to identify the pathway involved in caspase-1 activation induced by SLE serum in monocytes. RESULTS: Active caspase-1 in monocytes was upregulated in SLE patients. Cluster of differentiation 14 (CD14)-positive and CD16-positive monocytes showed considerable activation of caspase-1 compared with the other subsets of monocytes. Serum titres of anti-double stranded DNA antibodies were positively correlated with active caspase-1 in monocytes, and serum complement component 3 and platelet count were negatively correlated with active caspase-1 in monocytes. The SLE serum-induced activation of caspase-1 and IL-1ß secretion were down-regulated by inhibition of NLR family pyrin domain containing 3 (NLRP3), cyclic GMP-AMP synthase (cGAS), or stimulator of interferon genes (STING). CONCLUSIONS: These findings suggest that targeting inflammasome by regulating cGAS/STING and NLRP3 are potential therapeutic strategies for SLE.

Increased Proportion of CD226+ B Cells Is Associated With the Disease Activity and Prognosis of Systemic Lupus Erythematosus.

Background: CD226, an activating receptor expressed on the surface of natural killer (NK) cells and T cells, is also seen on B cells and CD226 polymorphism is associated with systemic lupus erythematosus (SLE). Because the specific roles of CD226+ B cells in SLE are still unknown, we investigated the association of CD226+ B cells with SLE. Methods: We measured CD226 expression on B cells and its subsets using flow cytometry in 48 SLE patients and 24 healthy controls (HCs). We assessed the relationships between CD226+ B cells and SLE Disease Activity Index 2000 (SLEDAI-2K), clinical manifestations, laboratory data, and prognosis after 12 months. Results: The proportions of CD226+ cells in whole B cells and all its subsets were significantly higher in SLE patients than HCs. In SLE patients, the proportions of CD226+ B cells and CD226+ switched-memory (SM) B cells were significantly correlated with SLEDAI-2K scores and anti-dsDNA antibody titers, and negatively correlated with serum complement levels. Moreover, basal percentages of CD226+ B cells and CD226+ SM B cells were low in patients who were in Lupus Low Disease Activity State after 12 months. In patients with renal involvement, the proportion of CD226+ B cells increased. Additionally, the proportion of CD226+ B cells was higher in patients who were not in complete renal remission after 12 months. Conclusions: Increased proportion of CD226+ B cells was associated with disease activity and prognosis of SLE. CD226+ B cells may be a useful biomarker for the management of SLE.

Association of elevated serum soluble CD226 levels with the disease activity and flares of systemic lupus erythematosus.

CD226 is an activating receptor expressed on the cell surface of natural killer cells and T cells. Although CD226 polymorphism is known to be involved in systemic lupus erythematosus (SLE), the involvement of soluble CD226 (sCD226) in SLE is still unknown. In the present study, we measured serum sCD226 levels using an enzyme-linked immunosorbent assay in 58 SLE patients and 33 healthy controls (HCs) and evaluated their associations with SLE Disease Activity Index 2000 (SLEDAI-2K), clinical manifestations, laboratory data, and the cumulative probability of flare. Serum sCD226 levels showed no significant differences between SLE patients and HCs. However, sCD226 levels were significantly elevated in active SLE patients with a SLEDAI-2K score of ≥ 20 compared with HCs. In SLE patients, sCD226 levels were significantly correlated with SLEDAI-2K scores and anti-dsDNA antibody titers. Moreover, the cumulative probability of flare was markedly higher in patients with high sCD226 than in those with low sCD226. In patients with neuropsychiatric involvement, sCD226 levels were elevated and reflected neuropsychiatric disease activity. These findings indicate that serum sCD226 levels are associated with disease activity and flares of SLE. Thus, it may be a useful biomarker for SLE, and its monitoring allows for more precise SLE management.

Use of 18F-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography to successfully diagnose central nervous system vasculitis in systemic lupus erythematosus and antiphospholipid syndrome: a case report.

A 53-year-old woman was admitted to our hospital for headache secondary to an acute subdural haematoma in the right cerebellar tentorium. She had been diagnosed with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) two years before presentation and was initiated on prednisolone (PSL) 40 mg/day as induction therapy, which was subsequently tapered to 5 mg/day. Her thrombocytopenia and renal impairment were managed by warfarin with a target prothrombin time-international normalised ratio of 2-3. Her history also included 5 instances of triggerless acute subdural haematoma in the right cerebellar tentorium in the preceding 8 months. Warfarin therapy was suspected as the cause of her bleeding; however, dose adjustment was ineffective. During the current admission, neither magnetic resonance imaging nor cerebral angiography could reveal the cause of the bleeding. However, spinal fluid IL-6 was 25.7 pg/mL, and 18F-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography showed fluorodeoxyglucose accumulation in the right medial occipital lobe cortex in the proximity of the haemorrhage site. Based on these two findings, we suspected vasculitis as the cause of recurrent bleeding. After ruling out malignancy, re-induction therapy with intravenous cyclophosphamide 500 mg/m2/month and PSL 30 mg/day was initiated. PSL was tapered to 2 mg/day and no signs of relapse have developed at 2 years after discharge. Her clinical course also supported vasculitis as the cause of recurrent central nervous system (CNS) bleeding and we discuss the usefulness of 18F-Fluorodeoxyglucose-Positron Emission Tomography in the diagnosis and treatment of CNS vasculitis in SLE and/or APS.

Homeostatic Milieu Induces Production of Deoxyribonuclease 1-like 3 from Myeloid Cells.

DNase 1-like 3 (DNase1L3), which belongs to DNase1 family, was originally identified as one of apoptosis- and necrosis-related endonucleases that fragmentate intranucleosomal DNA. A loss-of-function mutation has been reported in murine models of systemic lupus erythematosus (SLE) and in familial SLE patients. These reports suggest DNase1L3 plays an important role in the prevention of developing SLE; however, expression and function of DNase1L3 in human immune systems have been largely unclarified. As previous reports showed DNase1L3 is expressed in hematopoietic organs, we first analyzed expression levels of DNase1L3 in each subset of human peripheral blood cells by quantitative real-time PCR. Plasmacytoid dendritic cells showed the highest expression levels of DNase1L3 mRNA among peripheral blood cells. IL-4 enhanced DNase1L3 expression in monocytes, monocyte-derived dendritic cells, and monocyte-derived macrophages (MDMs), but not in T cells, B cells, or plasmacytoid dendritic cells. Together with IL-4, all-trans retinoic acid and apoptotic cells efficiently upregulated expression of DNalse1L3 in MDMs. As a result of intracellular signaling analysis, Jak1-IRS2-ERK/PI3K pathway was essential for IL-4-induced DNase1L3 expression. IL-4-treated monocyte-derived dendritic cells and MDMs secreted active DNase1L3 protein that could degrade liposome-DNA complexes, which were resistant to DNase1. Our results indicate DNase1L3 is secreted by innate immune cells and may play a critical role in the tissue homeostasis and on prevention of developing autoimmunity by degrading self-DNA.