Mitochondrial Plasticity and Glucose Metabolic Alterations in Human Cancer under Oxidative Stress-From Viewpoints of Chronic Inflammation and Neutrophil Extracellular Traps (NETs).

Oxidative stress elicited by reactive oxygen species (ROS) and chronic inflammation are involved both in deterring and the generation/progression of human cancers. Exogenous ROS can injure mitochondria and induce them to generate more endogenous mitochondrial ROS to further perpetuate the deteriorating condition in the affected cells. Dysfunction of these cancer mitochondria may possibly be offset by the Warburg effect, which is characterized by amplified glycolysis and metabolic reprogramming. ROS from neutrophil extracellular traps (NETs) are an essential element for neutrophils to defend against invading pathogens or to kill cancer cells. A chronic inflammation typically includes consecutive NET activation and tissue damage, as well as tissue repair, and together with NETs, ROS would participate in both the destruction and progression of cancers. This review discusses human mitochondrial plasticity and the glucose metabolic reprogramming of cancer cells confronting oxidative stress by the means of chronic inflammation and neutrophil extracellular traps (NETs).

Real-world risk factors for herpes zoster in patients with rheumatoid arthritis undergoing tofacitinib treatment.

BACKGROUND: This study sought to assess the risk factors of herpes zoster (HZ) in rheumatoid arthritis (RA) patients treated with tofacitinib (TOFA). METHODS: This retrospective study reviewed RA patients receiving TOFA. We compared clinical characteristics, laboratory profiles, concomitant medication use, and HZ incidence in patients with and without recent biologic synthetic disease-modifying anti-rheumatic drugs (bDMARDs) treatment, which is defined as their administration ≤ 180 days prior to the initiation of TOFA treatment. We used univariate Cox proportional hazards models and Kaplan-Meier analysis to assess risk factors. RESULTS: Among 304 RA patients, 97 had recent bDMARDs use and 207 did not. Patients with recent bDMARDs use typically had lower weekly doses of methotrexate, less hydroxychloroquine use, and shorter follow-up times. In the recent bDMARDs group, 64 (66.0%) used tumor necrosis factor inhibitors (TNFi), 19 (19.6%) used tocilizumab, and 14 (14.4%) used abatacept. The overall incidence rate (IR) of HZ was 5.62 per 100 person-years. Patients with recent bDMARDs use exhibited a higher HZ risk compared to those without recent bDMARDs use (IR ratio: 2.34, 95% confidence interval [CI]: 1.04-5.19, p = 0.028). Recent bDMARDs use (hazard ratio: 2.4, 95% CI: 1.12-4.95, p = 0.024) was an independent risk factor for HZ among multivariable analysis. Kaplan-Meier analysis confirmed increased HZ risk in RA patients on TOFA with recent bDMARDs use (log-rank p = 0.015). CONCLUSION: HZ is common in RA patients treated with TOFA, and recent bDMARDs (TNFi, tocilizumab and abatacept) use is a risk factor of HZ. HZ vaccination, therefore, should be recommended for this group.

Advanced Glycation End-Products Acting as Immunomodulators for Chronic Inflammation, Inflammaging and Carcinogenesis in Patients with Diabetes and Immune-Related Diseases.

Increased production of advanced glycation end products (AGEs) among reducing sugars (glucose, fructose, galactose, or ribose) and amino acids/proteins via non-enzymatic Maillard reaction can be found in lifestyle-related disease (LSRD), metabolic syndrome (MetS), and obesity and immune-related diseases. Increased serum levels of AGEs may induce aging, diabetic complications, cardiovascular diseases (CVD), neurodegenerative diseases (NDD), cancer, and inflamm-aging (inflammation with immunosenescence). The Maillard reaction can also occur among reducing sugars and lipoproteins or DNAs to alter their structure and induce immunogenicity/genotoxicity for carcinogenesis. AGEs, as danger-associated molecular pattern molecules (DAMPs), operate via binding to receptor for AGE (RAGE) or other scavenger receptors on cell surface to activate PI3K-Akt-, P38-MAPK-, ERK1/2-JNK-, and MyD88-induced NF-κB signaling pathways to mediate various pathological effects. Recently, the concept of "inflamm-aging" became more defined, and we have unveiled some interesting findings in relation to it. The purpose of the present review is to dissect the potential molecular basis of inflamm-aging in patients with diabetes and immune-mediated diseases caused by different AGEs.

Interstitial fibrosis increases the risk of end-stage kidney disease in patients with lupus nephritis.

OBJECTIVE: To evaluate the risk of end-stage kidney disease (ESKD) in LN patients using tubulointerstitial lesion scores. METHODS: Clinical profiles and histopathological presentations of 151 biopsy-proven LN patients were retrospectively examined. Risk factors of ESKD based on characteristics and scoring of their tubulointerstitial lesions [e.g. interstitial inflammation (II), tubular atrophy (TA) and interstitial fibrosis (IF)] were analysed. RESULTS: The mean age of 151 LN patients was 36 years old, and 136 (90.1%) were female. The LN cases examined included: class I/II (n = 3, 2%), class III/IV (n = 119, 78.8%), class V (n = 23, 15.2%) and class VI (n = 6, 4.0%). The mean serum creatinine level was 1.4 mg/dl. Tubulointerstitial lesions were recorded in 120 (79.5%) patients. Prior to receiving renal biopsy, nine (6.0%) patients developed ESKD. During the follow-up period (mean, 58 months), an additional 47 patients (31.1%) progressed to ESKD. Multivariate analyses identified serum creatinine [hazard ratio (HR): 1.7, 95% CI: 1.42-2.03, P < 0.001] and IF (HR: 3.2, 95% CI: 1.58-6.49, P = 0.001) as independent risk factors of ESKD. Kaplan-Meier analysis further confirmed a heightened risk of ESKD associated with IF. CONCLUSION: Tubulointerstitial involvement is commonly observed in the histopathological presentation of LN. However, IF, rather than II or TA, was found to increase the risk of ESKD in our cohort. Therefore, to predict renal outcome in LN patients prior to adjusting immunosuppressive treatment, the degree of IF should be reviewed.

The Risk Factors and Clinical Outcomes in Hepatitis B Seropositive and Seronegative Renal Transplant Patients.

INTRODUCTION: Hepatitis B virus (HBV) infection is prevalent in Asia including Taiwan. We retrospectively evaluated the risk of HBV reactivation and clinical outcomes in HBV+ and HBV- kidney transplant recipients. METHODS: Patients who underwent kidney transplantation between January 2004 and December 2021 were reviewed. The outcomes of interest included risks of HBV reactivation and patient/graft survival. RESULTS: We identified 337 patients (47.5 ± 12 years) in our final cohort. Fifty-two (15.4%) had hepatitis B surface antigen (HBsAg) positive at the time of transplantation. Seventeen developed viral reactivations, with 41.2% of them accompanied by active hepatitis. The graft survival, acute rejection rate, and cancer development after kidney transplantation did not differ in terms of HBsAg status. The Cox multivariate analysis indicated the HBV reactivation risk was increased by a lack of pretransplant anti-HBV medication (hazard ratio [HR], 5.95; 95% confidence interval [CI], 1.31-27.02; p = 0.021) or an absence of lifelong antiviral therapy (HR: 3.14; 95% CI: 1.01-9.74; p = 0.047). CONCLUSION: Individuals, independent of HBsAg status, had similar prognosis in terms of patient and graft survival, acute rejection rate, and cancer development. The absence of either pretransplant anti-HBV medication or lifelong antiviral therapy was significantly associated with an increased risk of HBV reactivation.

Antibodies against Small Ubiquitin-like Modifier Activating Enzyme May Be a Protective Factor from Rapid Progressive Interstitial Lung Disease in Patients Bearing Antibodies against Melanoma Differentiation Associated Gene 5.

Background: Anti-MDA5 antibody-bearing (anti-MDA5+)-dermatomyositis (DM) or polymyositis (PM) is notorious for causing rapidly progressive interstitial lung disease (RPILD) and/or cancers with high mortality rate. However, anti-MDA5 antibodies (Abs) are also found in other connective tissue diseases and their link with RPILD, especially with regard to the mortality rate, are unknown. Methods: We retrospectively recruited 71 patients bearing anti-MDA5-Abs in serum, stratified them in terms of a presence or absence of RPILD, and evaluated their clinical features, laboratory findings, associated myositis antibodies, concurrent connective tissue disease (CTD) as well as newly developed malignancies. Results: In total, 39 (55%) patients presented with DM/PM, but 32 (45%) did not. In total, 22 of the former and 11 of the latter developed RPILD eventually, accounting for a total of 46% of all MDA-5 bearing patients. On the other hand, 15 of all 71 (21.1%) patients had cancers. Among the 32 patients who did not have DM/PM, 27 (38.0% of all 71) had other CTDs, indicating that only 5 (7.0% of 71) patients did not have CTDs. Senility (odds ratio (OR) = 1.816, p = 0.032), presence of anti-Ro-52 antibody (OR = 1.676, p = 0.018), elevated C-reactive protein (CRP, OR = 4.354, p < 0.001) and carcinoembryonic antigen (CEA, OR = 2.625, p = 0.005) posed risks for RPILD. High lactose dehydrogenase (LDH, p = 0.009), CRP (p = 0.001) and CEA (p = 0.001), ferritin (p ≤ 0.001) and low albumin (p ≤ 0.001) were significantly associated with mortality. Anti-SAE antibodies were negatively correlated with RPILD as analyzed by univariate (OR = 0.245, p = 0.017) and multivariate (OR = 0.058, p = 0.036) regressions, indicating that they may be a protective factor in relation to RPILD (OR = 0.543, p = 0.008) or fatality (OR = 0.707, p = 0.012), which was also demonstrated in subgroup analyses. Conclusions: In contrast to various risk factors for RPILD or mortality, anti-SAE antibodies might conversely be a protective factor in anti-MDA5+ patients.

Risk Factors and Incidence of Serious Infections in Patients With Systemic Lupus Erythematosus Undergoing Rituximab Therapy.

OBJECTIVE: To evaluate the risk and protective factors of serious infection (SI) in patients with systemic lupus erythematosus (SLE) within 180 days of rituximab (RTX) treatment. METHODS: Patients with SLE treated with RTX were analyzed. SI was defined as any infectious disease requiring hospitalization. The clinical characteristics, laboratory profiles, medications, and incidence rate (IR) are presented. Multivariate Cox proportional hazards models and Kaplan-Meier analysis for risk factors of SI were performed. RESULTS: A total of 174 patients with SLE receiving RTX treatment were enrolled. The overall IR of SIs was 51.0/100 patient-years (PYs). Pneumonia (30.4/100 PYs), followed by soft tissue infections, intra-abdominal infections, and Pneumocystis jiroveci pneumonia (all 6.1/100 PYs) were the leading types of SIs. Twelve patients died during the 180-day follow-up (crude mortality rate: 14.6/100 PYs). Chronic kidney disease (CKD), defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m2 (hazard ratio [HR] 2.88, 95% CI 1.30-6.38), and a background prednisolone (PSL) equivalent dosage ≥ 15 mg/day (HR 3.50, 95% CI 1.57-7.78) were risk factors for SIs among all patients with SLE. Kaplan-Meier analysis confirmed the risk of SI for patients with SLE with CKD and a background PSL equivalent dosage ≥ 15 mg/day (log-rank P = 0.001 and 0.02, respectively). Hydroxychloroquine (HCQ) reduced the risk of SIs in patients with SLE (HR 0.35, 95% CI 0.15-0.82; log-rank P = 0.003). CONCLUSION: SI was prevalent in patients with SLE after RTX treatment. Patients with SLE with CKD and high-dose glucocorticoid use required constant vigilance. HCQ may reduce the risk of SI among patients with SLE administered RTX.

Immune-mediated diseases after vaccinations with AZD1222, BNT-162b2, &/or mRNA-1273: An observational investigation of 78 patients.

BACKGROUND: Immune-mediated diseases (IMDs) after nucleic acid-based vaccines have been sporadically reported since their introduction during the worldwide COVID-19 crisis. Confirming their cause-effect association remains challenging. We analysed the effects of AZD1222 (ChAdOx1 nCoV-19), BNT-162b2, and/or mRNA-1273 on the development &/or deterioration of IMDs in terms of the time of clinical onsets of IMDs after exposure to these vaccines. METHODS: We retrospectively reviewed 78 in-patients in Taipei Veterans General Hospital, who presented with IMDs within 120 days after receiving AZD1222, BNT-162b2, &/or mRNA-1273 vaccinations in Taiwan from May 2021 to April 2022. The duration from inoculation to development of IMD was analysed by two-tailed Kolmogorov-Smirnov (K-S) test for goodness of fit. RESULTS: The average time to new IMDs or flare-up of the diseases following vaccinations was 36 ± 26 days for all 91 events in these 78 patients. The onset time of IMDs after vaccinations was not haphazard as analysed by two-tailed K-S test for overall 91 events (40 new and 51 deteriorating episodes, p < 0.001). The IMDs presenting as non-connective tissue diseases (non-CTDs) have a shorter duration of incubation after vaccinations than those of CTDs (<14.7 days, 95 % confidence interval [CI], 3.0 to 26.4, p = 0.014). Furthermore, systemic vasculitis and type 2 inflammatory diseases were observed exclusively in those receiving AZD1222. CONCLUSION: AZD1222, BNT-162b2, or mRNA-1273 influence the activities of IMDs in ways yet to be explored. High index of suspicion to IMDs after nucleic acid-based vaccine inoculation against COVID-19 may be important for primary care physicians.

The Taiwanese Map of Axial Spondyloarthritis: Living with the Condition.

Background and Objective: The International Map of Axial Spondyloarthritis (IMAS) explores the physical, psychological, and social experiences of patients with axial spondyloarthritis (axSpA). This initiative is now being expanded to Taiwan as the Taiwanese Map of Axial Spondyloarthritis (TMAS). We aim to provide rheumatologists with insights into the perspectives of Taiwanese patients, enabling physicians to better understand the unmet needs of these patients and optimize their management. Materials and Methods: The TMAS is a cross-sectional study gathering data through an online survey of axSpA patients, promoted by the Ankylosing Spondylitis Caring Society of R.O.C. (ASCARES), conducted from July 2017 to March 2018 by Ipsos, and analyzed by the Health & Territory Research (HTR) group of the University of Seville. The questionnaire includes 99 questions that cover domains such as patient profile, diagnosis, habits/lifestyle, employment status, physical/psychological health status, social support, use of healthcare services, and treatments. Results: A total of 112 axSpA patients were included in this survey. The mean age was 38.6 years and 75.0% were male. The average diagnostic delay was 3 years, and 19.6% reported extra-articular manifestations. Out of the 49 respondents who reported HLA-B27 information, 35 were HLA-B27-positive. The disease burden was high, with a mean BASDAI score of 4.9 and 75.9% having a mild to moderate degree of spinal stiffness. Furthermore, they were socially and psychologically burdened, with 88.4% experiencing work-related issues and 25.9% suffering from anxiety. Conclusions: The TMAS sheds light on the overall perspective of axSpA patients in Taiwan. The TMAS shows shorter diagnostic delay compared to patients from the EMAS. However, high disease activity and significant psychological distress still trouble the patients, causing functional impairments and even leading to career failures. Understanding the perspective of axSpA patients can help rheumatologists adjust treatment strategies to their unmet needs and improve their disease outcomes.

Rituximab induction and reinduction in granulomatosis with polyangiitis and microscopic polyangiitis: A retrospective multicenter study in Taiwan.

OBJECTIVES: This study aimed to investigate the clinical outcomes of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) under rituximab induction and reinduction therapy in Taiwan. METHODS: We performed a retrospective study in patients with GPA or MPA receiving rituximab therapy from August 2008 to July 2020 in seven medical centers in Taiwan. The clinical characteristics and outcomes of these patients were analyzed. RESULTS: In total, 53 patients (18 with GPA and 35 with MPA) were included. Kidney involvement (82.9% vs. 22.2%, p < .001) and initial creatinine (3.25 ± 2.37 vs. 1.07 ± 0.82, p < .001) were significantly higher in MPA. Within 24 weeks after the first course of rituximab, there were seven deaths (five due to infection and two due to active disease) in patients with MPA (7/35, 20%) compared to 0 in patients with GPA. Of 33 patients receiving rituximab for kidney involvement, 23 survived and were free from renal replacement therapy at 24 weeks. Their chronic kidney disease (CKD) stages improved in 2 but progressed in 7, while 24 had stable CKD stages. Death or end-stage renal disease (ESRD) was associated with infection and higher initial creatinine. Reinduction therapy for relapse was required in 18 (39.1%) of 46 survivors, which was associated with anti-proteinase 3 (PR3) positive (odds ratio 3.667, p = .049) and younger age with a cutoff of 49.4 (AUC = 0.679, p = .030, sensitivity = 66.67%, specificity = 75%). CONCLUSION: Significant mortality occurred after rituximab induction, especially in patients with MPA. In survivors, age younger than 50 and anti-PR3 positive were associated with the risk of relapse requiring reinduction.

Decipher the Immunopathological Mechanisms and Set Up Potential Therapeutic Strategies for Patients with Lupus Nephritis.

Lupus nephritis (LN) is one of the most severe complications in patients with systemic lupus erythematosus (SLE). Traditionally, LN is regarded as an immune complex (IC) deposition disease led by dsDNA-anti-dsDNA-complement interactions in the subendothelial and/or subepithelial basement membrane of glomeruli to cause inflammation. The activated complements in the IC act as chemoattractants to chemically attract both innate and adaptive immune cells to the kidney tissues, causing inflammatory reactions. However, recent investigations have unveiled that not only the infiltrating immune-related cells, but resident kidney cells, including glomerular mesangial cells, podocytes, macrophage-like cells, tubular epithelial cells and endothelial cells, may also actively participate in the inflammatory and immunological reactions in the kidney. Furthermore, the adaptive immune cells that are infiltrated are genetically restricted to autoimmune predilection. The autoantibodies commonly found in SLE, including anti-dsDNA, are cross-reacting with not only a broad spectrum of chromatin substances, but also extracellular matrix components, including α-actinin, annexin II, laminin, collagen III and IV, and heparan sulfate proteoglycan. Besides, the glycosylation on the Fab portion of IgG anti-dsDNA antibodies can also affect the pathogenic properties of the autoantibodies in that α-2,6-sialylation alleviates, whereas fucosylation aggravates their nephritogenic activity. Some of the coexisting autoantibodies, including anti-cardiolipin, anti-C1q, anti-ribosomal P autoantibodies, may also enhance the pathogenic role of anti-dsDNA antibodies. In clinical practice, the identification of useful biomarkers for diagnosing, monitoring, and following up on LN is quite important for its treatments. The development of a more specific therapeutic strategy to target the pathogenic factors of LN is also critical. We will discuss these issues in detail in the present article.

Cytokines and regulatory T cells in ankylosing spondylitis.

To investigate the correlations among cytokines and regulatory T cells (T-regs) in ankylosing spondylitis (AS) patients, and their changes after anti-tumour necrosis factor-α (TNF-α) treatment. We included 72 AS patients with detailed medical records, disease activity score (Bath Ankylosing Spondylitis Disease Activity Index), functional index (Bath Ankylosing Spondylitis Functional Index), and laboratory data (interleukin (IL)-2, IL-4, IL-10, TNF-α, interferon (IFN)-γ, transforming growth factor (TGF)-ß, ESR, and CRP). Their peripheral blood mononuclear cells (PBMCs) were marked with anti-CD4, anti-CD25, and anti-FoxP3 antibodies, and triple positive T cells were gated by flow cytometry as T-regs. Their correlations were calculated and the changes after anti-TNF-α therapy were compared. The frequency of T-regs in PBMCs was positively correlated to ESR and CRP in AS (r = 0.35 and 0.43; p = 0.032 and 0.027, respectively), and there was also a significant correlation between serum level of TNF-α and CRP (p = 0.041). The frequency of T-regs in PBMCs positively correlated to serum levels of TNF-α, IL-10, and TGF-ß, while IL-2, IL-4, and IFN-γ showed opposite results. After anti-TNF-α treatment, there were significantly lower serum levels of TNF-α, IL-10, TGF-ß, and frequency of T-regs in PBMCs among these AS patients (p = 0.026, 0.032, 0.029, and 0.037, respectively). In AS patients, proinflammatory cytokine may give positive feedback to induce more T-reg production and anti-inflammatory cytokine secretion to suppress this inflammatory status, and they can be reversed by anti-TNF-α therapy. However, the detailed interactions among T-regs and complex cytokine networks in autoinflammatory diseases still need more studies and further functional assay.

2023 Taiwan Society of Cardiology (TSOC) and Taiwan College of Rheumatology (TCR) Joint Consensus on Connective Tissue Disease-Associated Pulmonary Arterial Hypertension.

Background: Pulmonary arterial hypertension (PAH), defined as the presence of a mean pulmonary artery pressure > 20 mmHg, pulmonary artery wedge pressure ≤ 15 mmHg, and pulmonary vascular resistance (PVR) > 2 Wood units based on expert consensus, is characterized by a progressive and sustained increase in PVR, which may lead to right heart failure and death. PAH is a well-known complication of connective tissue diseases (CTDs), such as systemic sclerosis, systemic lupus erythematosus, Sjogren's syndrome, and other autoimmune conditions. In the past few years, tremendous progress in the understanding of PAH pathogenesis has been made, with various novel diagnostic and screening methods for the early detection of PAH proposed worldwide. Objectives: This study aimed to obtain a comprehensive understanding and provide recommendations for the management of CTD-PAH in Taiwan, focusing on its clinical importance, prognosis, risk stratification, diagnostic and screening algorithm, and pharmacological treatment. Methods: The members of the Taiwan Society of Cardiology (TSOC) and Taiwan College of Rheumatology (TCR) reviewed the related literature thoroughly and integrated clinical trial evidence and real-world clinical experience for the development of this consensus. Conclusions: Early detection by regularly screening at-risk patients with incorporations of relevant autoantibodies and biomarkers may lead to better outcomes of CTD-PAH. This consensus proposed specific screening flowcharts for different types of CTDs, the risk assessment tools applicable to the clinical scenario in Taiwan, and a recommendation of medications in the management of CTD-PAH.

Gouty arthritis involves impairment of autophagic degradation via cathepsin D inactivation-mediated lysosomal dysfunction that promotes apoptosis in macrophages.

This study examined autophagy-lysosome pathway (ALP) perturbations in synovial monocytes/macrophages from patients with gouty arthritis (GA) and the associations of ALP perturbations with cell death. Synovial fluid mononuclear cells (SFMCs) and synovial tissues (STs) from patients with GA, as well as monosodium urate (MSU) crystal-exposed macrophages, underwent immunoblotting, quantitative polymerase chain reaction, and immunofluorescence analyses of markers linked to the ALP (microtubule-associated protein 1 light chain 3B [LC3B], p62, cathepsin D [CTSD], and lysosome-associated membrane protein 2 [LAMP2]) and cell death (caspase-3). GA STs underwent immunohistochemistry and immunofluorescence analyses to determine the distributions of LC3B-positive autophagosomes and macrophages. GA SFMCs and STs exhibited impaired autophagic degradation, indicated by elevated levels of LC3B and p62, along with CTSD upregulation and caspase-3 activation. Macrophages from GA STs exhibited significant accumulation of LC3B-positive autophagosomes. The temporal effects of MSU crystals on the ALP and the associations of these effects with cell death were investigated using a macrophage model of GA. MSU crystal-exposed macrophages exhibited early (2 h) autophagosome formation but later (6-24 h) autophagic flux impairment, demonstrated by p62 accumulation, lysosomal inhibitor failure to increase LC3B accumulation, and LC3B colocalization with p62. These macrophages exhibited autophagic flux impairment because of CTSD inactivation-mediated lysosomal dysfunction, which caused immature CTSD to accumulate within damaged LAMP2-positive lysosomes. This accumulation coincided with caspase-3-dependent cell death (24 h) that was unaffected by CTSD inhibition. These findings indicate that GA involves MSU crystal-induced impairment of autophagic degradation via CTSD inactivation-mediated lysosomal dysfunction, which promotes apoptosis in macrophages.

A Functional Polymorphism Downstream of Vitamin A Regulator Gene CYP26B1 Is Associated with Hand Osteoarthritis.

While genetic analyses have revealed ~100 risk loci associated with osteoarthritis (OA), only eight have been linked to hand OA. Besides, these studies were performed in predominantly European and Caucasian ancestries. Here, we conducted a genome-wide association study in the Han Chinese population to identify genetic variations associated with the disease. We recruited a total of 1136 individuals (n = 420 hand OA-affected; n = 716 unaffected control subjects) of Han Chinese ancestry. We carried out genotyping using Axiom Asia Precisi on Medicine Research Array, and we employed the RegulomeDB database and RoadMap DNase I Hypersensitivity Sites annotations to further narrow down our potential candidate variants. Genetic variants identified were tested in the Geisinger's hand OA cohort selected from the Geisinger MyCode community health initiative (MyCode®). We also performed a luciferase reporter assay to confirm the potential impact of top candidate single-nucleotide polymorphisms (SNPs) on hand OA. We identified six associated SNPs (p-value = 6.76 × 10-7-7.31 × 10-6) clustered at 2p13.2 downstream of the CYP26B1 gene. The strongest association signal identified was rs883313 (p-value = 6.76 × 10-7, odds ratio (OR) = 1.76), followed by rs12713768 (p-value = 1.36 × 10-6, OR = 1.74), near or within the enhancer region closest to the CYP26B1 gene. Our findings showed that the major risk-conferring CC haplotype of SNPs rs12713768 and rs10208040 [strong linkage disequilibrium (LD); D' = 1, r2 = 0.651] drives 18.9% of enhancer expression activity. Our findings highlight that the SNP rs12713768 is associated with susceptibility to and severity of hand OA in the Han Chinese population and that the suggested retinoic acid signaling pathway may play an important role in its pathogenesis.

NLRP12 is an innate immune checkpoint for repressing IFN signatures and attenuating lupus nephritis progression.

Signaling driven by nucleic acid sensors participates in interferonopathy-mediated autoimmune diseases. NLRP12, a pyrin-containing NLR protein, is a negative regulator of innate immune activation and type I interferon (IFN-I) production. Peripheral blood mononuclear cells (PBMCs) derived from systemic lupus erythematosus (SLE) patients expressed lower levels of NLRP12, with an inverse correlation with IFNA expression and high disease activity. NLRP12 expression was transcriptionally suppressed by runt-related transcription factor 1-dependent (RUNX1-dependent) epigenetic regulation under IFN-I treatment, which enhanced a negative feedback loop between low NLRP12 expression and IFN-I production. Reduced NLRP12 protein levels in SLE monocytes was linked to spontaneous activation of innate immune signaling and hyperresponsiveness to nucleic acid stimulations. Pristane-treated Nlrp12-/- mice exhibited augmented inflammation and immune responses; and substantial lymphoid hypertrophy was characterized in NLRP12-deficient lupus-prone mice. NLRP12 deficiency mediated the increase of autoantibody production, intensive glomerular IgG deposition, monocyte recruitment, and the deterioration of kidney function. These were bound in an IFN-I signature-dependent manner in the mouse models. Collectively, we reveal a remarkable link between low NLRP12 expression and lupus progression, which suggests the impact of NLRP12 on homeostasis and immune resilience.

Health-related quality of life improvement by adalimumab therapy in patients with rheumatoid arthritis in Taiwan: A nationwide prospective study.

BACKGROUND: To determine the effects of adalimumab on health-related quality of life (HRQoL) in Taiwanese patients with moderate-to-severe rheumatoid arthritis (RA) (NCT02616380). METHODS: During a 24-week observational period, 100 biologic-naive patients with RA received 40 mg adalimumab subcutaneously, every 2 weeks. The primary endpoint was a change in Health Assessment Questionnaire-Disability Index (HAQ-DI) score at 24 weeks. The secondary endpoints included change in HAQ-DI at week 12, number and percentage of patients achieving a meaningful improvement in HAQ-DI at weeks 12 and 24, and changes in the 36-Item Short Form Health Survey (SF-36), EuroQol 5-dimension 3-level version (EQ-5D-3L) index, and Work Productivity and Activity Impairment (WPAI) questionnaire scores at weeks 12 and 24. RESULTS: At weeks 12 and 24, mean changes in HAQ-DI from baseline were -0.34 ± 0.46 and -0.44 ± 0.59 (both p < 0.001), and clinically meaningful improvement in HAQ-DI was achieved by 60.4% and 59.6% of patients, respectively. SF-36, EQ-5D-3L index, and WPAI scores significantly improved ( p < 0.001) from baseline to weeks 12 and 24. Exploratory analyses showed diabetes was significantly associated with changes in HAQ-DI, EQ-5D-3L, and WPAI scores whereas peptic ulcer correlated with changes in the SF-36 physical component summary T-score. CONCLUSION: HRQoL improved after initiation of adalimumab therapy in Taiwanese patients with moderate-to-severe RA.

Risk factors for mortality in systemic lupus erythematosus patients: Analysis of adult and pediatric cohorts in Taiwan.

BACKGROUND: Overall survival of systemic lupus erythematosus (SLE) patients significantly increased in recent decades, however, the relative risk of mortality is still high. Long-term survival outcome of pediatric SLE remains unclear. This study aims to explore the long-term survival rate and its predictors in patients with systemic lupus erythematosus (SLE). METHODS: A retrospective, hospital-based cohort study was performed between 2004 and 2018 in a tertiary referral medical center in Taiwan. Data on comorbidities, medications, and causes of admission were collected for risk factor analysis using time-dependent multivariate Cox proportional hazards models. RESULTS: A total of 2392 adults and 115 pediatric SLE patients were enrolled (female, n = 2157 and 95, respectively). The 10-year survival rates were 93.2%, 90.2%, 98.9%, and 100% in adult women, adult men, girls, and boys with SLE, respectively. The overall mortality rate was 2.09 case/100 patient-years (PY) for male SLE and 1.39 case/100 PY for female SLE patients. Male SLE patients did not have a statistically significantly higher mortality rate than female SLE patients in each age stratification. Infectious disease (n = 119), heart failure (n = 21), and cerebrovascular accident (n = 14) were the leading causes of death in adult SLE patients. Advanced age (hazard ratio [HR]: 1.04, 95% confidence interval [CI]: 1.03-1.05), treatment with mean dosage of systemic glucocorticoid equivalent to >10 mg/d of prednisolone (HR: 1.71, 95% CI: 1.14-2.57), comorbidities with malignancy (HR: 1.94, 95% CI: 1.22-3.09), chronic kidney disease (HR: 1.86, 95% CI: 1.25-2.77), hypertension (HR: 1.42, 95% CI: 1.01-1.98), and admission due to bacterial pneumonia (HR: 1.92, 95% CI: 1.12-3.31) and sepsis (HR: 2.78, 95% CI: 1.51-5.13) were independent risk factors for mortality in SLE patients. CONCLUSION: SLE patients with advanced age, malignancy, chronic kidney disease, hypertension, treated with a higher average dosage of glucocorticoids, and admission due to bacterial pneumonia and sepsis have an increased risk of mortality.