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Abstract Background Hyperactive neutrophil extracellular traps (NETs) formation plays a crucial role in active severe systemic lupus erythematosus (SLE). However, what triggers the imbalance in dysregulated NETs formation in SLE is elusive. Transfer RNA-derived small RNAs (tsRNAs) are novel non-coding RNAs, which participate in various cellular processes. We explore the role of tsRNAs on NETs formation in SLE. Methods We analyzed the levels of NETs DNA and platelet-derived extracellular vesicles (pEVs) from 50 SLE patients and 20 healthy control subjects. The effects of pEVs on NETs formation were evaluated by using immunofluorescence assay and myeloperoxidase-DNA PicoGreen assay. The regulatory mechanism of pEVs on NETs formation and inflammatory cytokines production were investigated using an in vitro cell-based assay. Results Increased circulating NETs DNA and pEVs were shown in SLE patients and were associated with disease activity (P

Abstract Notwithstanding recent advances in direct antiviral specialists (DAAs) for hepatitis C infection (HCV), it is yet a pervasive overall issue in patients with rheumatoid arthritis (RA). Exosomal microRNAs (miRNAs) is associated with HCV infection. However, it remains unknown how miRNAs respond following biologic disease-modifying antirheumatic drug (bDMARD) and targeted synthetic DMARD (tsDMARD) treatment in HCV patients with RA. We prospectively recruited RA patients taking anti-tumor necrosis factor-α (TNF-α) inhibitors rituximab (RTX) and tofacitinib. The serum hepatitis C viral load was measured using real-time quantitative reverse transcriptase PCR before and 6 months after bDMARD and tsDMARD therapy. HCV RNA replication activity was measured using an HCV-tricistronic replicon reporter system, and quantitative analysis of hsa-mir-122-5p and hsa-mir-155-5p in patients was performed using quantitative PCR. HCV RNA replication in hepatocytes was not affected by tofacitinib or TNF-α inhibitor treatment. Hsa-mir-155-5p and hsa-mir-122-5p were significantly expanded in RA patients with HCV as compared with those without HCV. We observed a dramatic increase in hsa-mir-122-5p and a decrease in hsa-mir-155-5p expression levels in patients taking RTX in comparison with other treatments. Finally, a reduction in hsa-mir-122-5p and an increase in hsa-mir-155-5p were observed in a time-dependent manner after tofacitinib and DAA therapy in RA-HCV patients. These results showed that hsa-mir-155-5p and hsa-mir-122-5p were significantly increased in RA-HCV patients as compared with those without HCV after taking tofacitinib. Hsa-mir-155-5p and hsa-mir-122-5p may be potential biomarkers for treatment efficacy in RA patients with HCV.

Abstract Background Hyperactive neutrophil extracellular traps (NETs) formation plays a key role in the pathogenesis of severe COVID-19. Extracellular vesicles (EVs) are vehicles which carry cellular components for intercellular communication. The association between COVID-19 patients-derived EVs and NETs formation remains elusive. Methods We explored the roles of EVs in NETs formation from 40 COVID-19 patients with different disease severities as well as 30 healthy subjects. The EVs-carried microRNAs profile was analyzed using next generation sequencing approach which was validated by quantitative reverse transcription PCR. The regulatory mechanism of EVs on NETs formation was investigated by using an in vitro cell-based assay, including immunofluorescence assay, flow cytometry, and immunoblotting. Results COVID-19 patient–derived EVs induced NETs formation by endocytosis uptake. SARS-CoV-2 spike protein-triggered NETs formation was significantly enhanced in the presence of platelet–derived EVs (pEVs) and this effect was Toll-like receptor (TLR) 7/8- and NADPH oxidase-dependent. Increased levels of miR-21/let-7b were revealed in EVs from COVID-19 patients and were associated with disease severity. We demonstrated that the spike protein activated platelets directly, followed by the subsequent intracellular miR-21/let-7b upregulation and then were loaded into pEVs. The pEVs-carried miR-21 interacted with TLR7/8 to prime p47phox phosphorylation in neutrophils, resulting in NADPH oxidase activation to promote ROS production and NETs enhancement. In addition, miR-21 modulates NF-κB activation and IL-1β/TNFα/IL-8 upregulation in neutrophils upon TLR7/8 engagement. The miR-21 inhibitor and TLR8 antagonist could suppress efficiently spike protein-induced NETs formation and pEVs primed NETs enhancement. Conclusions We identified SARS-CoV-2 triggered platelets–derived GU-enriched miRNAs (e.g., miR-21/let-7b) as a TLR7/8 ligand that could activate neutrophils through EVs transmission. The miR-21-TLR8 axis could be used as a potential predisposing factor or therapeutic target for severe COVID-19.

Primary Sjogren’s syndrome (pSS) is often concomitant with fibromyalgia (FM). Salivary gland sonography aids in the diagnosis of pSS. We aimed to discover, in primary FM patients, the presence of pSS in undiagnosed patients through salivary gland sonography. We prospectively recruited 42 primary FM patients. FM symptoms were evaluated based on the revised Fibromyalgia Impact Questionnaire (FIQR). Salivary gland sonography was performed. Patients with positive findings underwent salivary gland biopsy. Comparisons were undertaken using the Mann–Whitney U tests and Chi-squared test. In primary FM patients, the prevalence of dry eye was 83%, and dry mouth was 90%. The salivary gland sonographic score did not differ between patients with and without dry eye/mouth. One patient with a positive finding at salivary gland sonography had a positive result of salivary gland biopsy. In the other four patients who received salivary gland biopsy, despite negative findings in salivary gland sonography, only one had a positive result of salivary gland biopsy. To be noted, scores evaluated by salivary gland sonography were negatively associated with levels of pain (rho = −0.360, p= 0.023) and levels of sleep quality (rho = −0.447, p = 0.004). Our pilot study demonstrated the potential of salivary gland biopsy in detecting undiagnosed pSS in primary FM patients.

Background: Volatile organic compounds (VOC) are major indoor air pollutants. Previous studies reported an association between VOC exposure and allergic diseases. Here, we aimed to explore the relationship between VOC exposure and atopic dermatitis (AD) in adults. Methods: We prospectively enrolled 31 adult AD patients and 11 healthy subjects as controls. Urine metabolite levels of VOCs, including 1.3-butadiene, acrylamide, benzene, toluene, and xylene, were all determined with liquid chromatography–mass spectrometry. The relationship between AD and log-transformed urine levels of VOC metabolites were examined using a multivariate linear regression model adjusted for age and sex. We also treated mouse bone marrow-derived cells (BMMCs) with 1,3-butadiene and toluene and measured the release of β-hexosaminidase. Results: Our results demonstrated that creatinine-corrected urine levels of N-Acetyl-S- (3,4-dihydroxybutyl)-L-cysteine (DHBMA), N-Acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L-cysteine (GAMA), and N-Acetyl-S-(benzyl)-L-cysteine (BMA) were all elevated in AD patients compared with controls. In a multivariate linear regression model, creatinine-corrected urine levels of BMA (a toluene metabolite) and DHBMA (a 1,3-butadiene metabolite) appeared elevated in AD patients, although statistical significance was not reached after correction for multiple comparisons. In addition, 1,3-butadiene and toluene could stimulate BMMCs to degranulate as much as compound 48/80. Conclusions: Some VOCs, such as 1,3-butadiene and toluene, might be associated with AD pathogenesis in adults.

Background Although the non-alcoholic fatty liver disease (NAFLD) is prevalent in the general population, NAFLD risk in newly diagnosed rheumatoid arthritis (RA) has rarely been explored. In this population-based cohort, we examined NAFLD risk in patients with RA and identified the potential risk factors.Design Retrospective study.Setting Taiwan.Participants 2281 newly diagnosed patients with RA and selected 91 240 individuals without RA to match with patients with RA (1:40) by age, gender, income status and urbanisation level of the residence.Outcomes In this retrospective study using the 2000–2018 claim data from two-million representative Taiwanese population, we identified and compared the incidence rates (IRs) of NAFLD and alcoholic fatty liver disease (AFLD) between RA and non-RA groups. Using multivariable regression analyses, we estimated adjusted HR (aHR) of NAFLD development in patients with RA compared with individuals without RA, with 95% CIs.Results The incidences of NALFD and AFLD were not significantly different between individuals with RA and without RA during the 17-year follow-up period. However, patients with RA had significantly increased NAFLD risk during the first 4 years after RA diagnosis, with IR ratio of 1.66 fold (95% CI 1.18 to 2.33, p

Abstract Introduction Elderly-onset rheumatoid arthritis (EORA) is associated with an increased mortality risk; however, the effect of conventional synthetic, biologics or targeted synthetic disease-modifying anti-rheumatic drugs (csDMARDs, bDMARDs or tsDMARDs) on the EORA-specific mortality risk is unknown. In this study, we investigated the risk factors for all-cause mortality of patients with EORA. Methods Data of EORA patients diagnosed with RA at age > 60 years between January 2007 and June 2021 were extracted from the electronic health record of Taichung Veterans General Hospital, Taiwan. Multivariable Cox regression was used to calculate the hazard ratio (HR) and 95% confidence interval (CI). The survival of patients with EORA was analyzed by Kaplan-Meier method. Results Among the 980 EORA patients who were enrolled (survivors 852 and non-survivor 128), the significant mortality-associated risk factors [HR (95% CI)] included higher age (1.10 [1.07–1.12], p

Abstract To investigate the impact of an electronic medical record management system (EMRMS) on disease activity and the frequency of outpatient visits among patients with ankylosing spondylitis (AS). We identified 652 patients with AS who were followed up for at least 1 year before and after the first Ankylosing Spondylitis Disease Activity Score (ASDAS) assessment and compared the number of outpatient visits and average visit time within 1 year before and after the initial ASDAS assessment. Finally, we analyzed 201 patients with AS who had complete data and received ≥ 3 continuous ASDAS assessments at an interval of 3 months, and we compared the results of the second and third ASDAS assessments with those of the first. The number of annual outpatient visits increased after ASDAS assessment (4.0 (4.0, 7.0) vs. 4.0 (4.0, 8.0), p

ABSTRACT Mixed cryoglobulinemia (MC) is a hepatitis C virus (HCV)–related extrahepatic manifestation that is characterized by the abnormal presence of immune complexes (ICs). This may be due to the reduced uptake and clearance of ICs. The C-type lectin member 18A (CLEC18A) is a secretory protein that is expressed abundantly in hepatocytes. We previously observed that CLEC18A increased significantly in the phagocytes and sera of patients with HCV, particularly those with MC. Herein, we explored the biological functions of CLEC18A in the MC syndrome development of patients with HCV by using an in vitro cell-based assay with quantitative reverse transcription-PCR, immunoblotting, immunofluorescence, flow cytometry, and enzyme-linked immunosorbent assays. HCV infection or Toll-like receptor 3/7/8 activation could induce CLEC18A expression in Huh7.5 cells. Upregulated CLEC18A interacts with Rab5 and Rab7 and enhances type I/III interferon production to inhibit HCV replication in hepatocytes. However, overexpressed CLEC18A suppressed phagocytic activity in phagocytes. Significantly decreased levels of the Fc gamma receptor (FcγR) IIA were found in the neutrophils of HCV patients, particularly in those with MC (P

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by chronic synovitis and the progressive destruction of cartilage and bone. RA is commonly accompanied by extra-articular comorbidities. The pathogenesis of RA and its comorbidities is complex and not completely elucidated. The assembly of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activates caspase-1, which induces the maturation of interleukin (IL)-1β and IL-18 and leads to the cleavage of gasdermin D with promoting pyroptosis. Accumulative evidence indicates the pathogenic role of NLRP3 inflammasome signaling in RA and its comorbidities, including atherosclerotic cardiovascular disease, osteoporosis, and interstitial lung diseases. Although the available therapeutic agents are effective for RA treatment, their high cost and increased infection rate are causes for concern. Recent evidence revealed the components of the NLRP3 inflammasome as potential therapeutic targets in RA and its comorbidities. In this review, we searched the MEDLINE database using the PubMed interface and reviewed English-language literature on the NLRP3 inflammasome in RA and its comorbidities from 2000 to 2023. The current evidence reveals that the NLRP3 inflammasome contributes to the pathogenesis of RA and its comorbidities. Consequently, the components of the NLRP3 inflammasome signaling pathway represent promising therapeutic targets, and ongoing research might lead to the development of new, effective treatments for RA and its comorbidities.

ABSTRACT Autophagy is a natural defense mechanism that protects the host against pathogens. We previously demonstrated that mycobacterial infection upregulated tumor necrosis factor-like weak inducer of apoptosis (TWEAK) to promote autophagy and mycobacterial autophagosome maturation through activation of AMP-activated protein kinase (AMPK). Fibroblast growth factor-inducible 14 (Fn14) is the receptor of TWEAK. But the role of Fn14 in mycobacterial infection remains elusive. Herein, we observed increased expression of Fn14 in peripheral blood mononuclear cells of active tuberculosis (TB) patients. Downregulation of cellular Fn14 enhanced mycobacterial survival in macrophages. Conversely, Fn14 overexpression inhibited mycobacterial growth, suggesting that Fn14 can inhibit mycobacterial infection. The in vitro results revealed that TWEAK-promoted mycobacterial phagosome maturation is Fn14-dependent. We demonstrated that TWEAK-Fn14 signaling promotes oxidative stress to enhance the expression of stromal interaction molecule 1 (STIM1) and its activation of the Ca2+ channel ORAI1. Elevated calcium influx stimulated the activation of CaMCCK2 (calcium/calmodulin-dependent protein kinase kinase 2) and its downstream effector AMPK, thus inducing autophagy in early infection. Persistently TWEAK-Fn14 signaling caused cell death in late infection by reducing mitochondrial membrane potential, leading to mitochondrial ROS accumulation, and activating cell death-associated proteins. Genetic Fn14 deficiency or TWEAK blockers decreased oxidative stress-induced calcium influx, thus suppressing autophagy and cell death in mycobacteria-infected macrophages, and resulting in elevated mycobacterial survival. We propose that the TWEAK-Fn14 axis and calcium influx could be manipulated for anti-TB therapeutic purposes. Our results offer a new molecular machinery to understand the association between the TWEAK-Fn14 axis, calcium influx, and mycobacterial infection. IMPORTANCE Tuberculosis remains a major cause of morbidity and mortality worldwide. We previously demonstrated a relationship between TWEAK and activation of the autophagic machinery, which promotes anti-mycobacterial immunity. The TWEAK-Fn14 axis is multi-functional and involved in the pathogenesis of many diseases, thus blockade of TWEAK-Fn14 axis has been considered as a potential therapeutic target. Here, we demonstrated that the TWEAK-Fn14 axis plays a novel role in anti-mycobacterial infection by regulating calcium-associated autophagy. Persistently, TWEAK-Fn14 signaling caused cell death in late infection by reducing mitochondrial membrane potential, leading to mitochondrial ROS accumulation, and activating cell death-associated proteins. TWEAK blocker or Fn14 deficiency could suppress oxidative stress and calcium-associated autophagy, resulting in elevated mycobacterial survival. We propose that the TWEAK-Fn14 axis and calcium influx could be manipulated for anti-TB therapeutic purposes. This study offers a new molecular machinery to understand the association between the TWEAK-Fn14 axis, calcium influx, and mycobacterial infection.

Introduction: Fibromyalgia (FM) is a chronic disorder characterized by widespread pain with an enormous symptom burden. Its treatment efficacy is limited. Its pathogenesis involves immune dysregulation, which includes interleukin-6 (IL-6) production. Methods: We herein reported a case series of FM patients receiving subcutaneous tocilizumab at our institution. FM symptoms were evaluated by the revised Fibromyalgia Impact Questionnaire (FIQR), which included pain level, and the fibromyalgianess scale based on the 2016 criteria of the American College of Rheumatology (ACR). FM symptoms were compared using the Wilcoxon signed-rank test. Neutrophils from primary FM patients and matched healthy controls were also isolated for transcriptome analysis. Results: We presented a total of two primary and four secondary FM patients who had received subcutaneous tocilizumab for a minimum of 12 weeks. All patients had severe symptoms despite standard treatments. Patients’ FIQR and fibromyalgianess both dropped at 4 and 12 weeks. Four (67%) of them reached a pain reduction of ≥30% at 4 weeks, and three (50%) reached a pain reduction of ≥30% at 12 weeks. Possible differentially expressed genes were identified in primary FM patients when compared with controls and after tocilizumab treatment. Conclusions: FM patients likely benefited from subcutaneous tocilizumab therapy. A randomized controlled trial is needed to verify its efficacy.

Rheumatoid arthritis (RA), a chronic inflammatory disease, carries a significant burden of atherosclerotic cardiovascular diseases (ASCVD). With their heterogeneous composition, high-density lipoprotein (HDL) particles have varied athero-protective properties, and some may even increase ASCVD risk. In this prospective and cross-sectional study, we aimed to examine the relationship between HDL sizes/metabolites and inflammation in RA. Using 1H-NMR-based lipid/metabolomics, differential HDL-related metabolites were identified between RA patients and healthy control (HC) subjects and between RA patients with and without anti-citrullinated peptide antibodies (ACPA). The correlation between the discriminative HDL-related metabolites and C-reactive protein (CRP) was evaluated in RA patients. RA patients demonstrated higher particle number, lipids, cholesterol, cholesterol ester, free cholesterol, and phospholipids in large/very large-sized HDLs. ACPA-positive patients had higher L-HDL-C and L-HDL-CE but lower small-/medium-sized HDL-TG levels than ACPA-negative patients. An inverse correlation was found between CRP levels and small-sized HDLs. Janus kinase inhibitor treatment was associated with increased serum small-sized HDL-related metabolites and decreased CRP levels. We are the first to reveal the significant associations between RA inflammation and HDL sizes/metabolites. A potential link between ACPA positivity and changes in serum levels of HDL-related metabolites was also observed in RA patients.

Abstract Modulation of miRNAs and neutrophil extracellular traps (NETs) formation are both implicated in inflammatory disorders. Adult-onset Still’s disease (AOSD) is a systemic autoinflammatory disease with neutrophilic leukocytosis and unknown etiology. Although the NETs formation is elevated in AOSD patients, the regulatory roles of miRNAs in NETs formation in AOSD remains unclear. We revealed that the circulating levels of IL-18, NETs, and miR-223 were significantly higher in active AOSD patients, compared with inactive AOSD patients or healthy controls (P

ObjectivesTo investigate the differences between the vector vaccine ChAdOx1 nCoV-19/AZD1222 (Oxford-AstraZeneca) and mRNA-based vaccine mRNA-1273 (Moderna) in patients with autoimmune rheumatic diseases (AIRD), and to explore the cell-cell interactions between high and low anti-SARS-CoV-2 IgG levels in patients with rheumatic arthritis (RA) using single-cell RNA sequencing (scRNA-seq).MethodsFrom September 16 to December 10, 2021, we consecutively enrolled 445 participants (389 patients with AIRD and 56 healthy controls), of whom 236 were immunized with AZD1222 and 209 with mRNA-1273. The serum IgG antibodies to the SARS-CoV-2 receptor-binding domain was quantified by electrochemiluminescence immunoassay at 4-6 weeks after vaccination. Moreover, peripheral blood mononuclear cells (PBMCs) were isolated from RA patients at 4-6 weeks after vaccination for scRNA-seq and further analyzed by CellChat. ScRNA-seq of PBMCs samples from GSE201534 in the Gene Expression Omnibus (GEO) database were also extracted for analysis.ResultsThe anti-SARS-CoV-2 IgG seropositivity rate was 85.34% for AIRD patients and 98.20% for healthy controls. The anti-SARS-CoV-2 IgG level was higher in patients receiving mRNA-1273 than those receiving AZD1222 (β: 35.25, 95% CI: 14.81-55.68, p=0.001). Prednisolone-equivalent dose >5 mg/day and methotrexate use in AIRD patients, and non-anti-tumor necrosis factor-α biologics and Janus kinase inhibitor use in RA patients were associated with inferior immunogenicity. ScRNA-seq revealed CD16-monocytes were predominant in RA patients with high anti-SARS-CoV2-IgG antibodies, and enriched pathways related to antigen presentation via MHC class II were found. HLA-DRA and CD4 interaction was enhanced in high anti-SARS-CoV2-IgG group.ConclusionsmRNA-1273 and AZD1222 vaccines exhibited differential immunogenicity in AIRD patients. Enriched pathways related to antigen presentation via MHC class II in CD16-monocytes might be associated with higher anti-SARS-CoV2-IgG level in RA patients and further study is warranted.

Context Alantolactone, the bioactive component in Inula helenium L. (Asteraceae), exhibits multiple biological effects. Objective We aimed to determine the anti-inflammatory effect of alantolactone in a collagen-induced arthritis (CIA) mouse model and its immunomodulatory effects on Th17 differentiation. Materials and methods A CIA mouse model was established with DBA/1 mice randomly divided into four groups (n = 6): healthy, vehicle and two alantolactone-treated groups (25 or 50 mg/kg), followed by oral administration of alantolactone to mice for 21 consecutive days after arthritis onset. The severity of CIA was evaluated by an arthritic scoring system and histopathological examination. Levels of cytokines and anti-CII antibodies as well as percentages of splenic Th17 and Th17 differentiation with or without alantolactone treatments (0.62, 1.2 or 2.5 μM) were detected with ELISA and flow cytometry, respectively. Western blot analysis was used to evaluate intracellular signalling in alantolactone-treated spleen cells. Results In CIA mice, alantolactone at 50 mg/kg attenuated RA symptoms, including high arthritis scores, infiltrating inflammatory cells, synovial hyperplasia, bone erosion and levels of the proinflammatory cytokines TNF-α, IL-6 and IL-17A, but not IL-10 in paw tissues. Alantolactone also reduced the number of splenic Th17 cells and the capability of naïve CD4+ T cells to differentiate into the Th17 subset by downregulating STAT3/RORγt signalling by as early as 24 h of treatment. Discussion and conclusions Alantolactone possesses an anti-inflammatory effect that suppresses murine CIA by inhibiting Th17 cell differentiation, suggesting alantolactone is an adjunctive therapeutic candidate to treat rheumatoid arthritis.

ObjectivesThe Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) has been widely utilized to evaluate disease activity in patients with ankylosing spondylitis (AS) by an arbitrary cut-off of ≥4 to indicate high disease activity and initiate biological therapy. The Ankylosing Spondylitis Disease Activity Score (ASDAS) is a new composite index to assess AS disease activity states that have been defined and validated. ASDAS ≥2.1 was selected as a criterion to start biological therapy. The purpose of this study was to estimate the corresponding BASDAI and ASDAS cut-off in a Taiwanese AS cohort.MethodsFrom November 2016 to October 2018, we assessed the ASDAS and the BASDAI regularly and recorded demographic data for 489 AS patients in Taichung Veterans General hospital (TCVGH) using an electronic patient-reported data system linked to electronic medical records. We used receiver operating characteristic curves with Youden's J statistic to determine the BASDAI values that correspond to ASDAS disease activity cut-offs (i.e., 1.3, 2.1, and 3.5).ResultsIn our population, the best trade-off BASDAI values corresponding to ASDAS -C-reactive protein (CRP) 1.3, 2.1, and 3.5 were 2.1, 3.1, and 3.7, respectively. The optimal BASDAI values corresponding to ASDAS-erythrocyte sedimentation rates 1.3, 2.1, and 3.5 were 2.0, 2.6, and 4.8, respectively.ConclusionWe propose a revised BASDAI cut-off based on our data, as BASDAI scores are commonly used globally. A more reasonable, lower BASDAI cut-off to initiate or change biological therapy will bring us closer to better decisions to treat AS patients.

ABSTRACT There are large gaps in understanding the molecular machinery accounting for the association of hepatitis C virus (HCV) infection with autoimmunity. Mixed cryoglobulinemia (MC) is the most common HCV-associated extrahepatic manifestation, which is characterized by B-cell lymphoproliferation and autoantibody production. B-cell activating factor (BAFF) is a member of the tumor necrosis factor family and plays an important role in B-cell proliferation. We explored the roles of hepatocyte-derived exosomal microRNAs (exo-miRNAs) and BAFF in the extrahepatic diseases of HCV infection. The exo-miRNA profiles were explored using a next-generation sequencing approach, followed by quantitative reverse transcription-PCR validation. The Toll-like receptor 7 (TLR7) polymorphism were analyzed using quantitative PCR. The biological function of exo-miRNAs and TLR7 polymorphism in BAFF expression was evaluated by using immunoblotting and enzyme-linked immunosorbent assay. Significantly increased levels of BAFF, exosomes, and TLR7 were found in HCV patients, particularly in those with MC (P

Different subsets of dendritic cells (DCs) participate in the development of rheumatoid arthritis (RA). In particular, myeloid DCs play a key role in the generation of autoreactive T and B cells. Herein, we undertook a literature review on those synthetic and natural compounds that have therapeutic efficacy/potential for RA and act through the regulation of myeloid DCs. Most of these compounds inhibit both the maturation of DCs and their secretion of inflammatory cytokines and, subsequently, alter the downstream T-cell response (suppression of Th1 and Th17 responses while expanding the Treg response). The majority of the synthetic compounds are approved for the treatment of patients with RA, which is consistent with the importance of DCs in the pathogenesis of RA. All of the natural compounds are derived from plants. Their DC-modulating effect has been demonstrated both in vitro and in vivo. In addition, these natural products ameliorate arthritis in rodents and are potential therapeutics for human RA.

Objectives: To investigate factors associated with major adverse cardiovascular events (MACEs) in patients with rheumatoid arthritis (RA). Methods: We conducted a nationwide, population-based, case-control study using Taiwan’s National Health Insurance Research Database for 2003–2013. From 2004 to 2012, we identified 108,319 newly diagnosed RA patients without previous MACEs, of whom 7,580 patients (7.0%) developed MACEs during follow-up. From these incident RA patients, we included 5,994 MACE cases and 1:4 matched 23,976 non-MACE controls for analysis. The associations of MACEs with comorbidities and use of anti-rheumatic medications within 1 year before the index date were examined using conditional logistic regression analyses. Results: Using multivariable conditional logistic regression analysis, the risk of MACE in RA patients was associated with use of golimumab [odd’s ratio (OR), 0.09; 95% confidence interval (CI), 0.01-0.67], abatacept (OR, 0.13; 95% CI, 0.02–0.93), hydroxychloroquine (OR, 0.90; 95% CI, 0.82-0.99), methotrexate (OR, 0.72; 95% CI, 0.64–0.81), cyclosporin (OR, 1.43; 95% CI, 1.07–1.91), nonsteroidal anti-inflammation drugs (NSAIDs) (OR, 1.36; 95% CI, 1.27–1.46), antiplatelet agent (OR, 2.47; 95% CI, 2.31-2.63), hypertension (without anti-hypertensive agents: OR, 1.04; 95% CI, 0.96-1.12; with anti-hypertensive agents: OR, 1.47; 95% CI, 1.36-1.59), diabetes (OR, 1.27; 95% CI, 1.18-1.37), hyperlipidemia without lipid-lowering agents (OR, 1.09; 95% CI, 1.01-1.17), ischemic heart disease (OR, 1.20; 95% CI, 1.10-1.31), and chronic obstructive pulmonary disease (COPD) (OR, 1.12; 95% CI, 1.03-1.23) in the parsimonious model. The risk of MACE in RA patients also increased markedly in participants younger than 65 years with some comorbidities. Conclusions: This population-based case-control study revealed that the use of golimumab, abatacept, hydroxychloroquine, and methotrexate were associated with a decreased risk of MACE development in newly diagnosed RA patients, while the use of cyclosporin, NSAIDs, and antiplatelet agents, and comorbidities, including hypertension, diabetes, hyperlipidemia without lipid-lowering agent therapy, ischemic heart disease, and COPD, were associated with an increased risk of MACE development in RA patients.

Objective: Primary Sjögren's syndrome (pSS) is characterized by exocrine glandular inflammation; however, the association between preceding mammary-gland-inflammation-related diseases and newly diagnosed pSS remains unexplored.Methods: We used the 2003–2013 data retrieved from Taiwan's National Health Insurance Research Database (NHIRD) to conduct the present population-based study. We identified newly diagnosed pSS female patients during the 2001–2013 period, as well as age-matched (1:20) and propensity-score-matched (1:2) non-SS individuals (as controls). We explored the associations between pSS and a history of mastitis and fibrocystic breast disease by determining adjusted odds ratios (aORs) with 95% confidence intervals (CIs) using a conditional logistical regression analysis after controlling for potential confounders.Results: We identified 9,665 patients with pSS and 193,300 age-matched non-SS controls, as well as 9,155 SS cases and 18,310 propensity-score-matched non-SS controls. We found that fibrocystic breast disease (aOR, 1.75; 95% CI, 1.63–1.88) were independently associated with incident SS, whereas mastitis and childbirth-associated breast infections were not associated with incident SS. We also found positive associations between SS and previously reported SS-associated diseases, including cardiovascular diseases, thyroid diseases, pancreatitis, bronchiectasis, infectious diseases, osteoporosis, and ankylosing spondylitis. In the propensity-score-matched populations, the associations between pSS and fibrocystic breast disease (aOR, 1.74; 95% CI, 1.58–1.91) remained consistent.Conclusion: The present population-based study revealed a previously unexplored association between pSS and history of fibrocystic breast disease, and the finding highlights the need to survey pSS in patients with mammary-gland-inflammation-associated diseases.

Abstract Background Increasing evidence indicates a pathogenic role of deregulated autophagy in rheumatoid arthritis (RA). We examined the relationship between autophagy and inflammatory parameters in patients with RA receiving biologic therapy. Methods In 72 patients with RA and 20 healthy control subjects (HC), autophagosome levels were determined by the mean fluorescence intensity (MFI) of autophagosomotropic dye incorporated into circulating immune cells, and p62 expression levels in immune cells were measured by flow cytometry. We used immunoblotting to examine protein expression of LC3-II and p62 in peripheral blood mononuclear cells. Results Patients with RA had significantly higher levels of autophagosome reflected by MFI of Cyto-ID in circulating lymphocytes, monocytes, and granulocytes (median values, 3.6, 11.6, and 64.8, respectively) compared with HC (1.9, 6.0, and 35.8; respectively) (all p

Background: Numerous cases of the coronavirus disease 2019 (COVID-19) with autoimmune and rheumatic manifestations have been reported. Despite the available reviews that summarized its autoimmune/rheumatic manifestations, a systematic approach is still lacking. Therefore, we conducted a comprehensive systematic review in order to give an overview upon these rare but clinically significant manifestations.Methods: We performed a literature search of PubMed and EMBASE as of October 9, 2020. All articles relevant to either systemic or organ-specific autoimmune and rheumatic manifestations potentially associated with COVID-19 were collected. The reviewed literature were limited to adults ≥18 years.Results: Although most of the existing evidence was based on case reports or case series without a long-term follow-up, a variety of autoimmune/rheumatic manifestations were associated with COVID-19. The manifestations that have a consistent association with COVID-19 include autoimmune cytopenia, cutaneous vasculitis, encephalitis, and Guillain-Barre syndrome. Such association is conflicting as regards to antiphospholipid syndrome, hemophagocytic lymphohistiocytosis, and myasthenia gravis.Conclusion: Our systematic review indicated the potential of the COVID-19 virus to trigger a myriad of autoimmune and rheumatic manifestations, which should be considered amid global efforts to combat COVID-19.

In this study we aimed to identify the predictors of drug survival for biologic and targeted synthetic DMARDs (bDMARDs and tsDMARDs) among patients with rheumatoid arthritis (RA) in a real-world setting. Data from RA patients receiving bDMARDs and tsDMARDs between 2007 and 2019 were extracted from the Taiwan Rheumatology Association Clinical Electronic Registry (TRACER). Patients were categorized into tumor necrosis factor-alpha (TNF-α) inhibitors, non-TNF-α inhibitors, and tofacitinib groups. The primary outcome was 3-year drug retention and the causes of bDMARDs and tsDMARDs discontinuation were recorded. Baseline demographic data before the initiation of bDMARDs and tsDMARDs treatment were analyzed to identify the predictors of 3-year drug survival. A total of 1,270 RA patients were recruited (TNF-α inhibitors: 584; non-TNF-α inhibitors: 535; tofacitinib: 151). The independent protective factors for 3-year drug survival were positive rheumatoid factor (RF) (HR: 0.48, 95% CI: 0.27-0.85, p = 0.013) and biologics-naïve RA (HR: 0.61, 95% CI: 0.39-0.94, p = 0.024). In contrast, positive anti-citrullinated protein antibody (ACPA) (HR: 2.24, 95% CI: 1.32-3.79, p = 0.003) and pre-existing latent tuberculosis (HR: 2.90, 95% CI: 2.06-4.09, p

Background: Vaccination is one of the most important measures worldwide to halt the spread of the corona virus disease 2019 (COVID-19). However, the efficacy and safety of these vaccines in rheumatic patients are not well explored. Therefore, we conducted a systematic review and meta-analysis. Methods: We performed a literature search of the PubMed and EMBASE databases on 17 November 2021. Forty-seven studies relevant to the immunogenicity, efficacy/effectiveness, and safety of COVID-19 vaccines were selected. Results: Our results demonstrated that COVID-19 vaccination is effective in protecting rheumatic patients from severe illness caused by the virus. Both the humoral and cellular immunogenicity of vaccines were impaired in rheumatic patients, which were greatly enhanced after the second vaccine dose. Receiving anti-CD20 therapy was associated with impaired humoral immunogenicity. Adverse events due to COVID-19 vaccines in rheumatic patients were similar to those in healthy controls, except for an increased incidence of arthralgia. The incidence of disease flares after COVID-19 vaccination was low. Conclusion: Our systematic review indicated the importance of full vaccination in rheumatic patients. Withholding anti-CD20 therapy was found to be potentially beneficial for the immunogenicity. Furthermore, the vaccines were found to be safe in general. Despite significant heterogeneity between studies, we recommend that rheumatic patients receive these vaccines amidst the global pandemic.

ObjectiveElevated tumour necrosis factor (TNF)-α has been implicated in the progression of liver fibrosis and pathogenesis of non-alcoholic fatty liver disease (NAFLD). We aim to investigate the impact of anti-TNF-α agents on the development of cirrhosis and NAFLD.DesignThis retrospective cohort study used a US claims database between 1 January 2010 and 31 December 2016. We identified adult patients with ankylosing spondylitis, inflammatory bowel disease, psoriatic arthritis or rheumatoid arthritis. Anti-TNF-α agents of interest included adalimumab, certolizumab, etanercept, golimumab and infliximab. The primary composite outcome was the development of new-onset cirrhosis, NAFLD or non-alcoholic steatohepatitis (NASH). The secondary outcomes were the development of (1) cirrhosis and (2) NAFLD or NASH. Propensity score for anti-TNF-α agent use was generated by logistic regression. Cox proportional hazard models adjusting for the propensity score were used with regard to time-varying anti-TNF-α agent exposure.ResultsThis study included 226 555 incident patients with immune-related diseases. During the median 1.5 years follow-up, there was an increased hazard with anti-TNF-α agent use in regard to liver outcomes (composite outcome HR: 1.47, 95% CI 1.27 to 1.70; cirrhosis HR 1.47, 95% CI 0.96 to 2.23; NAFLD or NASH HR 1.53, 95% CI 1.32 to 1.77). The composite outcome hazard was increased for each immune-related disease (HR 1.25–1.90).ConclusionIn the short term, we did not observe a beneficial effect of anti-TNF-α agent use for development of cirrhosis, NAFLD or NASH in patients with immune-related diseases.

ObjectiveTo assess the associations of the Assessment of Spondyloarthritis International Society Health Index (ASAS HI) with gender and other factors in patients with ankylosing spondylitis (AS).MethodsFrom November 2017 to October 2018, we measured the Ankylosing Spondylitis Disease Activity Score (ASDAS), the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI), the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) and the ASAS HI score for AS patients at the Taichung Veterans General Hospital. After adjusting for disease activity (ASDAS-erythrocyte sedimentation rate [ESR], ASDAS- C-reactive protein [CRP], BASDAI+ESR or BASDAI+CRP), mSASSS and other potential confounders including medications, comorbidities, and laboratory data, any associations between gender and the sum score of ASDAS HI were assessed using multiple linear regression analysis, as well as any associations between gender and an ASAS HI score >5 using multivariable logistic regression analysis.ResultsA total of 307 AS patients (62 [20.2%] females, mean age 46.4 years [S.D. 13.3], mean symptom duration 20.6 years [S.D. 12.1]) were included. Multiple linear regression analysis showed that the male gender was significantly associated with a lower ASAS HI (B = -1. 91, 95% confidence interval [CI], -2.82--1.00, p 5 than females (odds ratio = 0.15, 95% CI, 0.07-0.36, p ConclusionThis single-center, cross-sectional study revealed that a higher ASAS HI score was significantly associated with female gender and higher disease activity measures.

Background/Aims: Brachial–ankle pulse wave velocity (baPWV) reflects the stiffness of muscular arteries. Albuminuria is recognized as a marker of vascular dysfunction. We assessed the association between arterial stiffness and albuminuria in a population-based longitudinal study. Methods: 1116 adults aged ≥ 40 years in the Taichung Community Health Study (TCHS) in 2004 attended a follow-up visit in 2011. Albuminuria was defined as an urinary albumin-to-creatinine ratio (UACR) ≥ 30 mg/g. Arterial stiffness was defined as BaPWV ≥ 1540 cm/sec in males and BaPWV ≥ 1480 cm/sec in females, respectively. ∆baPWV was calculated as baPWV at follow-up minus baPWV at baseline, while ∆UACR was calculated as UACR at follow-up minus UACR at baseline. Multiple linear and logistic regression analyses were used to explore the relationship between albuminuria and arterial stiffness. Results: Among 652 subjects without arterial stiffness at baseline, 209 (32%) subjects developed incident arterial stiffness after an average of 6.6 years. In male subjects, baseline albuminuria was associated with development of arterial stiffness (odds ratio: 4.47, 95% confidence interval [CI]: 1.04–19.31) and ∆baPWV was modestly positively associated with ∆UACR. Conclusion: Our results indicated that male adults with albuminuria had an increased risk for developing arterial stiffness.

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by autoreactive B and T cells against β2-glycoprotein I (B2GPI), with vascular thrombosis or obstetrical complications. Dendritic cells (DCs) are crucial in the generation of autoimmunity. Here, we conducted a comprehensive systematic review on the relationship between DC and APS. We performed a literature search of PubMed as of 26 March 2021. A total of 33 articles were extracted. DCs are pivotal in inducing inflammatory responses and orchestrating adaptive immunity. DCs contribute to the local inflammation regarding vascular thrombosis or obstetrical complications. Both B2GPI and antiphospholipid antibodies (aPL) can promote antigen presentation by DCs and the generation or maintenance of autoimmunity. In addition, plasmacytoid DC activation is enhanced by aPL, thereby augmenting the inflammatory response. In line with these findings, DC modulation appears promising as a future treatment for APS. In conclusion, our review indicated the crucial role of DCs in the pathogenesis of APS. Deeper understanding of the complex relationship would help in developing new treatment strategies.

Abstract Adult-onset Still’s disease (AOSD) is a multi-systemic inflammatory disorder of unknown etiology. To date, no single diagnostic test is available for AOSD. Herein, we investigated the pathogenic role of microRNAs in AOSD. MicroRNA profiles in plasma from AOSD patients and healthy controls were analyzed by microarray analysis, followed by quantitative reverse transcription PCR validation. The biological functions of microRNAs were evaluated using in vitro cell-based assay. Among the differentially expressed microRNAs, microRNA-134 (miR-134) expression was positively correlated with AOSD activity scores and significantly decreased after effective treatment. An increased miR-134 level is significantly associated with the activation of Toll-like receptor 3 (TLR3). The reporter assay identified IL-18 binding protein (IL-18BP) as the target of miR-134. A negative correlation between miR-134 expression and IL-18BP mRNA levels were detected in peripheral blood cells following TLR3 ligand treatment. Lower plasma IL-18BP levels and higher IL-18 levels were also observed in active AOSD patients who had higher miR-134 expression than inactive patients. Upregulation of circulating miR-134 was associated with elevated IL-18 levels by targeting IL-18BP in AOSD patients and was positively correlated with disease activity, suggesting its involvement in AOSD pathogenesis. MiR-134 may be a novel activity indicator or potential prognostic biomarker in AOSD.

Kurarinone is a flavanone, extracted from Sophora flavescens Aiton, with multiple biological effects. Here, we determine the therapeutic potential of kurarinone and elucidate the interplay between kurarinone and the autoimmune disease rheumatoid arthritis (RA). Arthritis was recapitulated by induction of bovine collagen II (CII) in DBA/1 mice as a collagen-induced arthritis (CIA) model. After the establishment of the CIA, kurarinone was given orally from day 21 to 42 (100 mg/kg/day) followed by determination of the severity based on a symptom scoring scale and with histopathology. Levels of cytokines, anti-CII antibodies, and the proliferation and lineages of T cells from the draining lymph nodes were measured using ELISA and flow cytometry, respectively. The expressional changes, including STAT1, STAT3, Nrf2, KEAP-1, and heme oxygenase-1 (HO-1) changes in the paw tissues, were evaluated by Western blot assay. Oxidative stress featured with malondiadehyde (MDA) and hydrogen peroxide (H2O2) activities in paw tissues were also evaluated. Results showed that kurarinone treatment reduced arthritis severity of CIA mice, as well as their levels of proinflammatory cytokines, TNF-α, IL-6, IFN-γ, and IL-17A, in the serum and paw tissues. T cell proliferation was also reduced by kurarinone even under the stimulation of CII and anti-CD3 antibody. In addition, kurarinone reduced STAT1 and STAT3 phosphorylation and the proportions of Th1 and Th17 cells in lymph nodes. Moreover, kurarinone suppressed the production of MDA and H2O2. All while promoting enzymatic activities of key antioxidant enzymes, SOD and GSH-Px. In the paw tissues, upregulation of Nrf-2 and HO-1, and downregulation of KEAP-1 were observed. Overall, kurarinone showed an anti-inflammatory effect by inhibiting Th1 and Th17 cell differentiation and an antioxidant effect exerted in part through activating the Nrf-2/KEAP-1 pathway. These beneficial effects in CIA mice contributed to the amelioration of their arthritis, indicating that kurarinone might be an adjunct treatment option for rheumatoid arthritis.

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the production of β2-glycoprotein I (β2GPI)-dependent autoantibodies, with vascular thrombosis or obstetrical complications. Around 20% of APS patients are refractory to current treatments. Crassolide, a cembranoid diterpene extracted from soft corals, is a potential therapeutic candidate. Here, to examine the anti-inflammatory properties of crassolide, we first determined its effects on bone marrow-derived and splenic dendritic cells (DC). Specifically, we applied lipopolysaccharide (LPS) or β2GPI stimulation and measured the expressions of CD80 and CD86, and secretions of cytokines. We also determined in the OT-II mice, if bone marrow-derived DC was able to stimulate antigen-specific T cells. Moreover, we examined the therapeutic potential of crassolide postimmunization in a murine model of APS that depended on active immunization with β2GPI. The vascular manifestations were evaluated in terms of fluorescein-induced thrombi in mesenteric microvessels, whereas the obstetric manifestations were evaluated based on the proportion of fetal loss after pregnancy. We also measured blood titers of anti-β2GPI antibody, splenic cell proliferative responses and cytokine secretions after β2GPI stimulation ex vivo. Finally, we determined in these mice, hematological, hepatic and renal toxicities of crassolide. Crassolide after LPS stimulation suppressed DC maturation and secretion of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-12 and IL-23, and downstream T cell activation. Crassolide could partially ameliorate both the vascular and obstetric manifestations of APS in BALB/c mice. Both blood titers of anti-β2GPI antibody and splenic cell proliferation after β2GPI stimulation were reduced. Splenic Th1 and Th17 responses were also lowered after β2GPI stimulation. Finally, within therapeutic doses of crassolide, we found no evidence of its toxicity. In conclusion, we showed the ability of crassolide to suppress DC and downstream T cell responses. Crassolide is therefore a potential candidate for adjunctive therapy in APS.

Adult-onset Still’s disease (AOSD), an autoinflammatory disorder, is related to the dysregulation of NLR3-containing a pyrin domain (NLRP3)-inflammasome signaling. We aimed to investigate the associations of genetic polymorphisms of NLRP3-inflammasome signaling with AOSD susceptibility and outcome and to examine their functional property. Fifty-three candidate single-nucleotide polymorphisms (SNPs) involved in NLRP3-inflammasome response were genotyped using Sequenom MassArray on the samples from 66 AOSD patients and 128 healthy controls. The significant SNPs were validated by direct sequencing using a TaqMan SNP analyzer. Serum levels of associated gene products were examined by ELISA. One SNP rs11672725 of CARD8 gene was identified to be significantly associated with AOSD susceptibility by using MassArray and subsequent replication validation (p = 3.57 × 10−7; odds ratio 3.02). Functional assays showed that serum CARD8 levels were significantly lower in AOSD patients (median, 10,524.6 pg/mL) compared to controls (13,964.1 pg/mL, p = 0.005), while levels of caspase-1, IL-1β and IL-18 were significantly higher in patients (107.1 pg/mL, 2.1 pg/mL, and 1495.8 pg/mL, respectively) than those in controls (99.0 pg/mL, 1.0 pg/mL, and 141.4 pg/mL, respectively). Patients carrying rs11672725CC genotype had significantly higher serum caspase-1 and IL-18 levels (121.3 pg/mL and 1748.6 pg/mL) compared to those with CT/TT genotypes (72.6 pg/mL, p = 0.019 and 609.3 pg/mL, p = 0.046). A higher proportion of patients with rs11672725CC genotype had a systemic pattern of disease outcome, which was linked to low CARD8 levels. A novel variant, rs11672725, of the CARD8 gene was identified as a potential genetic risk for AOSD. Patients carrying the rs11672725CC genotype and C allele had low CARD8 levels, and were predisposed to a systemic pattern with an elevated expression of inflammasome signaling.

DNA vaccines have recently emerged as a therapeutic agent for treating autoimmune diseases, such as multiple sclerosis. Antiphospholipid antibody syndrome (APS) is an autoimmune disease characterized by β2-glycoprotein I (β2-GPI)-targeting antiphospholipid antibodies (APAs) and vascular thrombosis or obstetrical complications. To examine the therapeutic potential of a β2-GPI DNA vaccine, we administered a vaccine mixed with FK506 as an adjuvant to a mouse model of obstetric APS. First, the pCMV3-β2-GPI DNA vaccine, which encodes the full-length human β2-GPI gene, was constructed. Then, we administered the β2-GPI DNA vaccine in 0.1 ml of saline, mixed with or without 100 μg of FK506, intramuscularly to the mice on days 28, 35 and 42. Blood titers of the anti-β2-GPI antibody, platelet counts, activated partial thromboplastin times (aPTTs), and the percentage of fetal loss were measured. We also stimulated murine splenic T cells ex vivo with β2-GPI and determined the T helper cell proportion and cytokine secretion. The administration of the β2-GPI DNA vaccine mixed with FK506 reduced the blood IgG anti-β2-GPI antibody titers and suppressed APS manifestations in mice. The combination also suppressed interferon-γ and interleukin (IL)-17A secretion but increased the Treg cell proportion and IL-10 secretion in murine splenic T cells following ex vivo stimulation with β2-GPI. Our results demonstrated the therapeutic efficacy of a β2-GPI DNA vaccine and FK506 as an adjuvant in a murine model of obstetric APS. Possible mechanisms include the inhibition of Th1 and Th17 responses and the up-regulation of Treg cells.

Many studies have demonstrated elevated circulating levels of high-mobility group box 1 (HMGB1) and decreased circulating levels of soluble receptor for advanced glycation end products (sRAGE) in patients with autoimmune diseases. In the present study, we investigated plasma levels of both HMGB1 and sRAGE in primary antiphospholipid syndrome (pAPS) patients.We prospectively recruited 11 pAPS patients, 17 antiphospholipid antibody (APA)-positive SLE patients without APS manifestations (APA+SLE) and 12 SLE patients with secondary APS (APS+SLE). We also recruited 10 healthy controls (HCs). Plasma levels of HMGB1 and sRAGE were determined using sandwich ELISA kits. In addition, plasma levels of HMGB1 were also determined using Western blot in 6 pAPS patients and 6 HCs.There was no significant difference in plasma levels of HMGB1 measured by ELISA among subgroups of the enrolled subjects. In addition, there was no significant difference in plasma levels of HMGB1 measured by Western blot between pAPS patients and HCs. On the other hand, we observed a trend toward lower plasma levels of sRAGE in APA+SLE or APS+SLE patients when compared with HCs. However, there was no significant difference in plasma levels of sRAGE between pAPS patients and HCs, or between APA+SLE patients and APS+SLE patients.There was no significant difference in plasma levels of sRAGE or HMGB1 between pAPS patients and HCs. Plasma levels of sRAGE/HMGB1 could not be utilized to differentiate between APA+SLE and APS+SLE patients.

The objective of this study is to determine the risk of tuberculosis (TB) disease in biologics users among rheumatoid arthritis (RA) patients in Taiwan from 2000 to 2015. This retrospective cohort study enrolled adult RA patients initiated on first biologics at Taichung Veterans General Hospital. TB risks were determined as hazard ratio (HR) with 95% confidence interval (CI) using cox regression. A total of 951 patients were recruited; etanercept (n = 443), adalimumab (n = 332), abatacept (n = 74), golimumab (n = 60), tocilizumab (n = 31) and tofacitinib (n = 11). Twenty-four TB cases were identified; 13 in etanercept and 11 in adalimumab group with the TB incidence rate of 889.3/ 100,000 and 1055.6/ 100,000 patient-years respectively. There was no significant difference in TB risk between adalimumab and etanercept users with an incidence rate ratio of 1.27 (p = 0.556 by Poisson model). Significant 2-year TB risk factors included elderly patient >65 year-old (HR: 2.72, 95% CI: 1.06-6.99, p = 0.037), history of TB (HR: 6.24, 95% CI: 1.77-22.00, p = 0.004) and daily glucocorticoid use ≥5mg (HR:5.01, 95% CI: 1.46-17.21, p = 0.010). Sulfasalazine treatment appeared to be protective (HR: 0.32, 95% CI: 0.11-0.97, p = 0.043). Risk management plan (RMP) for TB before initiation of biologics commenced in 2012. The 2-year TB risks after RMP was compared with that before 2012 (HR:0.67, 95% CI: 0.30-1.49, p = 0.323). Elderly RA patients with a history of previous TB infection and concomitant moderate dose glucocorticoid were at higher risk of TB disease. Concurrent sulfasalazine treatment appeared to be a protective factor against TB disease.

Background: A higher fracture risk has been reported previously in patients with atopic dermatitis (AD). The bone mineral density (BMD) was not accounted for in these studies. Objective: To investigate the fracture risk in AD patients after adjustment for factors including BMD. Methods: We retrospectively analyzed AD patients (≥45 years) who underwent BMD examination at our hospital from July 2010 to February 2023. Individuals who received BMD examinations during a health checkup were identified as the controls. We documented their clinical characteristics, BMD, 10-year risk for a major fracture based on FRAX (Fracture Risk Assessment Tool), and development of osteoporotic fractures. Patients were followed until development of new onset fracture or the end of the study period. A cross-sectional comparison of BMD between AD patients and controls at baseline was performed using the Mann-Whitney U test after propensity score matching (PSM). Their fracture risks were compared using the multivariate Cox regression model. BMD and fracture risk were also compared between AD patients who received systemic therapy and those who did not. Results: A total of 50 AD patients and 386 controls were enrolled. The median age was older in AD patients when compared with controls (70 years vs 60 years). Their BMD at all sites was similar after PSM. After a median follow-up of 1.7-2.0 years, 13 osteoporotic fractures were identified. In the multivariate Cox regression analysis, AD was not associated with new onset fractures of all sites (adjusted hazard ratio [aHR] 2.55, 95% confidence interval [CI] 0.729.01) but was significantly associated with new onset vertebral fractures (aHR 6.80, 95% CI 1.77-26.17). The BMD and incidence of fractures were similar between AD who received systemic therapy and those who did not. Conclusions: Elderly AD patients had similar BMD but a higher short-term risk for vertebral fractures when compared with the controls. [ABSTRACT FROM AUTHOR]