Coexistence of Multiple Myositis-Specific Antibodies in Patients with Idiopathic Inflammatory Myopathies.

The mutual exclusivity of myositis-specific antibodies (MSAs) has been reported before, but the coexistence of 2 or more MSAs was still found in a few case reports. This study aims to confirm the existence and prevalence of double MSAs in patients with idiopathic inflammatory myopathy (IIM) and to clarify the clinical features of these patients. One hundred fifty-one patients with IIM diagnosed from 1 July 2018 to 31 July 2022, at National Cheng Kung University Hospital, Taiwan, were enrolled and divided into two groups, patients with ≤1 MSA (n = 128, 84.8%) and those with ≥2 MSAs (n = 23, 15.2%) according to the initial serology results. After being re-examined by ANA-IIF assay, 8 out of 23 patients were confirmed to have ≥2 MSAs. The demographic data and clinical features were presented. The prevalence of double-positive MSAs among IIM was 5.3% in this cohort. The coexistence of two MSAs in an IIM patient does exist but is rare. Patients with two MSAs belonging to two distinct IIM subtypes presented clinical features skewed to one subtype instead of "mixed phenotypes". No apparent difference in clinical severity was found between patients with ≥2 MSAs and ≤1 MSA. Longer follow-ups and more studies are required to characterize the patients of IIM with ≥2 MSAs.

Increased risk of early-onset childhood systemic lupus erythematosus for children born to affected parents: A nationwide child-parent cohort study.

Objective: Children of women with systemic lupus erythematosus (SLE) are at risk for childhood-onset SLE (cSLE). This study evaluated the incidence of early-onset cSLE and associated risk factors, including concomitant maternal and paternal autoimmune diseases, for these children. Methods: A population-based cohort study was conducted using national databases including the linked information of children and parents. Children of women with SLE and those of women without SLE were identified between 2004 and 2015. The cumulative cSLE incidence was estimated using the Kaplan-Meier method. The marginal Cox model was used to calculate the hazard ratio (HR) for cSLE events. Results: A total of 4,419 singletons of women with SLE and 1,996,759 singletons of women without SLE were identified. There were 9 (0.20%) and 503 (0.03%) incident cases of early-onset cSLE for offspring of women with and without SLE, respectively (incidence rate ratio, 8.34; 95% confidence interval [CI], 3.79-15.95]. The adjusted HR of incident cSLE in children of women with SLE was 4.65 (95% CI 2.11-10.24). Other risks for cSLE included pregnancy-induced hypertension/preeclampsia/eclampsia, paternal SLE, paternal Sjögren's syndrome (SS), and maternal SS. Conclusions: This national child-parent cohort study demonstrated that children of women with SLE are at significantly higher risk for cSLE during early childhood. Moreover, paternal SLE and parental SS increase the risk of cSLE for offspring.

Time-Dependent Analysis of Risk of New-Onset Heart Failure Among Patients With Polymyositis and Dermatomyositis.

OBJECTIVE: To determine the risk and time trends of heart failure (HF) leading to hospitalization in individuals newly diagnosed as having polymyositis/dermatomyositis (PM/DM) relative to non-PM/DM controls at the general population level. METHODS: A retrospective cohort study was conducted using data from a nationwide insurance database in Taiwan. Patients with incident PM/DM and without a history of HF were selected between 2000 and 2013. Unmatched and propensity score-matched cohorts were established separately. A multivariable Cox proportional hazards regression model was used to estimate the adjusted hazard ratio (HR) for the risk of HF in the unmatched cohort. In the propensity score-matched cohort, general population controls were selected and matched at a 1:1 ratio to the patients with PM/DM based on propensity scores, which accounted for the confounding factors of age, sex, index date (year) of first diagnosis, comorbidities, and medication usage. The cumulative incidence of HF was estimated using the Kaplan-Meier method. A stratified Cox proportional hazards model was used to calculate the HR for the risk of HF events at different follow-up time points among patients with PM/DM compared with non-PM/DM controls in the propensity score-matched cohort. RESULTS: In the unmatched cohort, the study assessed 2,025 patients with PM/DM and 196,109 general population controls. Results of multivariable Cox regression analysis, adjusted for age, sex, comorbidities, and medication usage, revealed a greater risk of HF leading to hospitalization in the PM/DM group than in the control group (adjusted HR 3.29, 95% confidence interval [95% CI] 2.60-4.18). After matching based on propensity score, a total of 1,997 pairs of PM/DM patients and general population controls were identified. In this propensity score-matched cohort, the cumulative incidence of HF in patients with PM/DM at 3 years, 5 years, and 10 years was 3.3%, 4.4%, and 7.4%, respectively. The absolute difference in HF risk in the PM/DM group compared with the control group was 1.8% at 3 years, 2.1% at 5 years, and 3.0% at 10 years. Compared with general population controls, patients with PM/DM exhibited an augmented risk of HF (HR 2.06, 95% CI 1.36-3.12). Analyses stratified according to follow-up time point revealed that the increased risk of HF persisted for up to 10 years after the PM/DM diagnosis. CONCLUSION: These results indicate that the risk of HF leading to hospitalization was increased in patients with PM/DM throughout the study period, supporting the need for greater vigilance in the monitoring of patients with PM/DM for the development of this potentially lethal complication.

NOX2-Deficient Neutrophils Facilitate Joint Inflammation Through Higher Pro-Inflammatory and Weakened Immune Checkpoint Activities.

Immune-mediated arthritis is an important chronic inflammatory disease of joints causing debilitating morbidity in affected patients. The mechanisms underlying immune-mediated arthritis have been intensively investigated, however the cellular and molecular factors contributing to the joint inflammation in different redox conditions have not been clearly elucidated. Previous research showed that phagocyte-produced reactive oxygen species (ROS) plays an anti-inflammatory role in K/BxN serum-transfer arthritis and NOX2-deficient mice tend to have more severe arthritis. Although many leukocytes play critical roles in the development of immune-mediated arthritis, the role of neutrophils, which are the main producers of ROS in inflammation, is still controversial. We hence assessed the immunomodulatory function of neutrophils from arthritic joints of NOX2-deficient and wild type mice in this study. We found more neutrophils accumulation in NOX2-deficient inflamed joints. RNA-sequencing and quantitative PCR revealed significantly increased expression of acute inflammation genes including IL1b, Cxcl2, Cxcl3, Cxcl10 and Mmp3 in activated neutrophils from the inflamed joints of NOX2-deficient mice. Moreover, gene set enrichment analysis (GSEA) showed enriched gene signatures in type I and II IFN responses, IL-6-JAK-STAT3 signaling pathway and TNF-α signaling pathway via NF-κB in NOX2-deficient neutrophils. In addition, we found that NOX2-deficient neutrophils expressed lower levels of PD-L1 and were less suppressive than WT neutrophils. Moreover, treatment of PD-L1-Fc decreased cytokine expression and ameliorated the severity of inflammatory arthritis. Our results suggest that NOX2-derived ROS is critical for regulating the function and gene expression in arthritic neutrophils. Both the strong pro-inflammatory and weakened anti-inflammatory functions of neutrophils due to abnormal redox regulation may be targets of treatment for immune-mediated arthritis.

Connective Tissue Disease-Associated Pulmonary Arterial Hypertension in Southern Taiwan: A Single-Center 10-Year Longitudinal Observation Cohort.

Background: Pulmonary arterial hypertension (PAH) is a life-threatening disease with different etiologies and outcomes. We aimed to explore differences in clinical features and outcomes of idiopathic PAH (iPAH) and connective tissue disease-related PAH (CTD-PAH) in Taiwanese patients and determine risk factors for mortality. Methods: We retrospectively reviewed the medical records of patients with right-sided heart catheterization-diagnosed PAH between January 2005 and December 2015. The iPAH (n = 31) and CTD-PAH (n = 14) patients were enrolled and followed until December 31, 2019. Between-group comparisons were conducted. Potential predictors of the mortality of PAH were determined using the Cox proportional hazard regression model. Results: CTD-PAH patients had higher levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and lower predicted diffusing capacity of carbon monoxide (DLCO) than iPAH patients. The mortality rates were similar between CTD-PAH and iPAH (21.4% vs. 22.6%, p = 0.99). A mean pulmonary arterial pressure (mPAP) > 46 mmHg was a predictor of PAH-induced mortality (adjusted hazard ratio 21.8, 95% confidence interval 2.32-204.8). Conclusions: A higher mPAP level, but not underlying CTDs, imposed a significantly increased risk of mortality to patients with PAH.

Is Behçet's syndrome associated with an increased risk of ischemic heart disease? A real-world evidence in Taiwan.

BACKGROUND: A variety of chronic inflammatory diseases are linked to ischemic heart disease (IHD); however, this association is less well studied in patients with Behçet's syndrome (BS). The primary objective of this study was to examine the impact of BS on the risk of IHD. The secondary objective was to estimate the long-term mortality risk in patients with BS. METHODS: Using a retrospective cohort design based on the Taiwan National Health Insurance Database, patients diagnosed with BS between 2000 and 2013, without prior history of IHD, were compared to non-BS individuals. The BS and non-BS cohorts were matched with a 1:2 ratio by propensity score, accounting for the following confounders: age, sex, year of index date, comorbidities, and drug exposure. Cox proportional hazard regression was used to derive the hazard ratio (HR) for IHD and mortality. The long-term survival rate was estimated using the Kaplan-Meier method. RESULTS: After propensity score matching, a total of 1554 patients newly diagnosed with BS and 3108 control subjects were identified. The incidence rate of IHD in the BS and control groups was 2.7 and 2.9 per 1000 person-years, respectively. The risk of IHD was comparable between BS and control cohorts [adjusted HR, 1.03; 95% confidence interval (CI), 0.66 to 1.62]. The 5- and 10-year survival rate of BS patients was 96.8% and 95.0%, respectively. Patients with BS exhibited a significantly higher risk of mortality than the sex- and age-matched general population (adjusted HR, 1.73; 95% CI, 1.30 to 2.32). CONCLUSION: Unlike other chronic systemic autoimmune disorders, BS does not appear to be associated with an excess risk of IHD.

Reduced Mortality Associated With the Use of Metformin Among Patients With Autoimmune Diseases.

Objective: Metformin has been linked to anti-proliferative and anti-inflammatory mechanisms. In this study, we aimed to examine the long-term impact of metformin on mortality and organ damage in patients with autoimmune diseases and type 2 diabetes mellitus (T2DM). Methods: We conducted a cohort study using the National Health Insurance Research Database in Taiwan between 1997 and 2013. Based on metformin and other anti-diabetic agent prescriptions, we categorized all patients with autoimmune diseases into either the metformin group (metformin administration for at least 28 days) or the non-metformin group. The primary outcomes were all-cause mortality and annual admission rate, while the secondary outcome was target organ damage. We followed patients from the index date to the date on which the event of interest occurred, death, or the end of this study. Results: Our cohort study included 3,359 subjects for analysis. During a mean follow up of 5.2 ± 3.8 years, the event rate of all-cause mortality was 228 (33.6%) in the metformin group and 125 (36.9%) in the non-metformin group. The risk of both all-cause mortality and annual number of admissions for autoimmune diseases was significantly lower in the metformin group than in the non-metformin group [hazard ratio (HR) 0.77; 95% CI 0.62-0.96 and risk ratio (RR) 0.81; 95% CI 0.73-0.90, respectively]. Conclusion: Metformin may add benefits beyond T2DM control with regard to reducing all-cause mortality and admission rate, as well as minimizing end-organ injury in lungs and kidneys among patients with autoimmune diseases.

Long-term renal prognosis among patients with primary Sjögren's syndrome and renal involvement: A nationwide matched cohort study.

BACKGROUND: The long-term renal outcome in patients with primary Sjögren's syndrome (pSS) remains uncertain. We aimed to determine the absolute incidence and relative risk of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in patients with pSS at the general population level. METHODS: We performed a retrospective cohort study using a national health insurance database in Taiwan from 2000 to 2013. We calculated the cumulative incidence of CKD and ESRD in our pSS and age-, sex- and entry time-matched control cohorts. Cox regression analyses were used to estimate adjusted hazard ratios (aHRs) after adjusting for comorbidities and medications. RESULTS: Among 17 505 patients with incident pSS, 1008 (5.8%) developed CKD and 38 (0.22%) developed ESRD. Of the 87 525 non-pSS controls, 3173 (3.6%) developed CKD and 256 (0.29%) developed ESRD. The risk of CKD was higher in patients with pSS than in the non-pSS controls (adjusted hazard ratio [HR] 1.49, 95% confidence interval [95% CI] 1.38-1.59). Notably, the risk of ESRD was similar in both pSS and non-pSS cohorts (aHR 0.82, 95% CI 0.58-1.16). CONCLUSIONS: Renal prognosis among patients with pSS and renal involvement is good. Although the risk of ESRD did not increase in patients with pSS, a significantly increased risk of CKD was observed in these patients, indicating the need for increased vigilance in regular monitoring for renal complications in patients with pSS.

SOX4 activates CXCL12 in hepatocellular carcinoma cells to modulate endothelial cell migration and angiogenesis in vivo.

The overexpression of SOX4 in various kinds of cancer cells was associated with poor prognosis for patients. The role of SOX4 in angiogenesis and tumor microenvironment modulation was recently documented in breast cancer but remains unclear in hepatocellular carcinoma (HCC). In our study, the clinical relevance of SOX4 overexpression in HCC and its role in the tumor microenvironment were investigated. The overexpression of SOX4 (SOX4high) in tumor lesions was associated with higher microvessel density (P = 0.012), tumor thrombosis formation (P = 0.012), distant metastasis (P < 0.001), and an independent prognostic factor for disease-free survival in HCC patients (P = 0.048). Endogenous SOX4 knockout in Hep3B cells by the CRISPR/cas9 system reduced the expression of CXCL12, which, in turn, attenuated chemotaxis in human umbilical vein endothelial cells, tube formation in vitro, reduced tumor growth, reticular fiber production, and angiogenesis in vivo in a xenograft mouse model. Treatment with an antagonist targeting CXCR4 (AMD3100), a receptor of CXCL12, inhibited chemotaxis and tube formation in endothelial cells in vitro. The CXCL12 promoter was activated by ectopic expression of a Flag-tagged SOX4 plasmid, endogenous SOX4 knockdown abolished promoter activity of CXCL12 as shown by luciferase assays, and an association with the CXCL12 promoter was identified via chromatin immunoprecipitation in HCC cells. In conclusion, SOX4 modulates the CXCL12 promoter in HCC cells. The secretory CXCL12, in turn, modulates CXCR4 in endothelial cells, reticular fibers to regulate the tumor microenvironment and modulate neovascularization, which might contribute to the distant metastasis of tumors.

How mycobacteria take advantage of the weakness in human immune system in the modern world.

Tuberculosis (TB) infection remains a global health threat in recent decades partly due to a marked increase in the number of susceptible patients, including those with diabetes mellitus (DM) and who receive biologics. Immunity in TB infection is complex as Mycobacterium tuberculosis (MTB) is a highly adaptive pathogen and may evade the immune defense through various ways. Recent advances in TB immunity have revealed that granulomatous inflammation in TB infection is highly dynamic and the early influx of neutrophils may lead to excessive inflammation and pulmonary cavitation, which provide niches for MTB not only to survive but also to spread to other sites. Furthermore, reactive oxygen species have been found to play a crucial role among pathogenesis of TB infection in diabetics (DM-TB) through regulating inflammasome activation and the production of IL-1ß, which in turn modulates the inflammatory network in TB infection, leading to dysfunctional inflammatory responses and tissue remodeling. To understand the exact immunological mechanisms underlying TB infection hence is essential for developing novel adjunctive host-directed therapy (HDT) aiming to alleviate excessive inflammation and tissue destruction and, at the same time, enhance the efficacy of currently available choices of anti-mycobacterial agents. Here we reviewed current epidemiological challenges of global TB control, novel immunological mechanisms underlying dysregulated inflammation in TB infection, especially in DM-TB, and some potential applications of adjunctive HDT in TB treatment.

Incidence and survival impact of pulmonary arterial hypertension among patients with systemic lupus erythematosus: a nationwide cohort study.

BACKGROUND: No population-based study has investigated the cumulative incidence of pulmonary arterial hypertension (PAH) in patients with newly diagnosed systemic lupus erythematosus (SLE) or the survival impact of PAH in this population. METHOD: We used a nationwide database in Taiwan and enrolled incident SLE patients between January 1, 2000, and December 31, 2013. The cumulative incidence of PAH in the SLE patients and the survival of these patients were estimated by the Kaplan-Meier method. Potential predictors of the development of PAH were determined using a Cox proportional hazards regression model. RESULTS: Of 15,783 SLE patients, 336 (2.13%) developed PAH. The average interval from SLE diagnosis to PAH diagnosis was 3.66 years (standard deviation [SD] 3.36, range 0.1 to 13.0 years). Seventy percent of the patients developed PAH within 5 years after SLE onset. The 3- and 5-year cumulative incidence of PAH were 1.2% and 1.8%, respectively. Systemic hypertension was an independent predictor of PAH occurrence among the SLE patients (adjusted hazard ratio 2.27, 95% confidence interval 1.59-2.97). The 1-, 3-, and 5-year survival rates of SLE patients following the diagnosis of PAH were 87.7%, 76.8%, and 70.1%, respectively. CONCLUSIONS: PAH is a rare complication of SLE and the majority of PAH cases occur within the first 5 years following SLE diagnosis. Systemic hypertension may be a risk factor for PAH development in the SLE population. The overall 5-year survival rate after PAH diagnosis was 70.1%.

Label-free glucose detection using cantilever sensor technology based on gravimetric detection principles.

Efficient maintenance of glucose homeostasis is a major challenge in diabetes therapy, where accurate and reliable glucose level detection is required. Though several methods are currently used, these suffer from impaired response and often unpredictable drift, making them unsuitable for long-term therapeutic practice. In this study, we demonstrate a method that uses a functionalized atomic force microscope (AFM) cantilever as the sensor for reliable glucose detection with sufficient sensitivity and selectivity for clinical use. We first modified the AFM tip with aminopropylsilatrane (APS) and then adsorbed glucose-specific lectin concanavalin A (Con A) onto the surface. The Con A/APS-modified probes were then used to detect glucose by monitoring shifts in the cantilever resonance frequency. To confirm the molecule-specific interaction, AFM topographical images were acquired of identically treated silicon substrates which indicated a specific attachment for glucose-Con A and not for galactose-Con A. These results demonstrate that by monitoring the frequency shift of the AFM cantilever, this sensing system can detect the interaction between Con A and glucose, one of the biomolecule recognition processes, and may assist in the detection and mass quantification of glucose for clinical applications with very high sensitivity.

The adsorptive capacity of vapor-phase mercury chloride onto powdered activated carbon derived from waste tires.

Injection of powdered activated carbon (PAC) upstream of particulate removal devices (such as electrostatic precipitator and baghouses) has been used effectively to remove hazardous air pollutants, particularly mercury-containing pollutants, emitted from combustors and incinerators. Compared with commercial PACs (CPACs), an alternative PAC derived from waste tires (WPAC) was prepared for this study. The equilibrium adsorptive capacity of mercury chloride (HgCl2) vapor onto the WPAC was further evaluated with a self-designed bench-scale adsorption column system. The adsorption temperatures investigated in the adsorption column were controlled at 25 and 150 degrees C. The superficial velocity and residence time of the flow were 0.01 m/sec and 4 sec, respectively. The adsorption column tests were run under nitrogen gas flow. Experimental results showed that WPAC with higher Brunauer-Emmett-Teller (BET) surface area could adsorb more HgCl2 at room temperature. The equilibrium adsorptive capacity of HgCl2 for WPAC measured in this study was 1.49 x 10(-1) mg HgCl2/g PAC at 25 degrees C with an initial HgCI2 concentration of 25 microg/m3. With the increase of adsorption temperature < or = 150 degrees C, the equilibrium adsorptive capacity of HgCl2 for WPAC was decreased to 1.34 x 10(-1) mg HgCl2/g PAC. Furthermore, WPAC with higher sulfur contents could adsorb even more HgCl2 because of the reactions between sulfur and Hg2+ at 150 degrees C. It was demonstrated that the mechanisms for adsorbing HgCl2 onto WPAC were physical adsorption and chemisorption at 25 and 150 degrees C, respectively. Experimental results also indicated that the apparent overall driving force model appeared to have the good correlation with correlation coefficients (r) > 0.998 for HgCl2 adsorption at 25 and 150 degrees C. Moreover, the equilibrium adsorptive capacity of HgCl2 for virgin WPAC was similar to that for CPAC at 25 degrees C, whereas it was slightly higher for sulfurized WPAC than for CPAC at 150 degrees C.

Partition and size distribution of heavy metals in the flue gas from municipal solid waste incinerators in Taiwan.

This study investigates the partition of heavy metals in both solid and gas phases in the flue gas from municipal solid waste (MSW) incinerators. Six MSW incinerators in Taiwan were examined and heavy metals in the flue gas at the inlets and outlets of air pollution control devices (APCDs) were analyzed. Heavy metals including Hg, Pb, Cd, Zn, Cu and Cr were sampled by USEPA Method 29 and further analyzed using inductively coupled plasma-mass spectroscopy (ICP-MS) and cold vapor atomic absorption spectrometry (CVAAS). Experimental results revealed that the removal efficiencies of the APCDs for the heavy metals Pb, Cd, Zn, Cu and Cr greatly exceeded 90%, but that of Hg did not. Two groups of heavy metals upstream of APCDs were observed. Pb, Cd, Zn, Cu and Cr were present mainly in the solid phase with a solid to gas ratio (S/G) of over 12.3. However, in most cases, mercury appeared mainly in the gas phase with an S/G ratio from 0.15 to 1.04, because it has a low boiling point. Additionally, treatment with the APCDs increased the S/G ratio of mercury because gaseous mercury could be removed by injecting powdered activated carbon (PAC) into the flue gas. Moreover, the distribution of particle sizes in the solid phase was bimodal. Finer particles (d(p)2.5 microm) contained more Cr and Hg.

Preparation of sulfurized powdered activated carbon from waste tires using an innovative compositive impregnation process.

The objective of this study is to develop an innovative compositive impregnation process for preparing sulfurized powdered activated carbon (PAC) from waste tires. An experimental apparatus, including a pyrolysis and activation system and a sulfur (S) impregnation system, was designed and applied to produce sulfurized PAC with a high specific surface area. Experimental tests involved the pyrolysis, activation, and sulfurization of waste tires. Waste-tire-derived PAC (WPAC) was initially produced in the pyrolysis and activation system. Experimental results indicated that the Brunauer-Emmett-Teller (BET) surface area of WPAC increased, and the average pore radius of WPAC decreased, as water feed rate and activation time increased. In this study, a conventional direct impregnation process was used to prepare the sulfurized PAC by impregnating WPAC with sodium sulfide (Na2S) solution. Furthermore, an innovative compositive impregnation process was developed and then compared with the conventional direct impregnation process. Experimental results showed that the compositive impregnation process produced the sulfurized WPAC with high BET surface area and a high S content. A maximum BET surface area of 886 m2/g and the S content of 2.61% by mass were obtained at 900 degrees C and at the S feed ratio of 2160 mg Na2S/g C. However, the direct impregnation process led to a BET surface area of sulfurized WPAC that decreased significantly as the S content increased.