HBV reactivation in HBsAg-/HBcAb+ rheumatoid arthritis patients receiving biologic/targeted synthetic DMARDs.

BACKGROUND: Rheumatoid arthritis (RA) patients seropositive for hepatitis B core antibody (HBcAb) and negative for hepatitis B surface antigen (HBsAg) are at risk of hepatitis B virus (HBV) reactivation when treated with biologic or targeted synthetic (b/ts) disease-modifying antirheumatic drugs (DMARDs). The study aims to investigate the risk in this population. METHODS: From January 2004 through December 2020, 1068 RA patients undergoing b/tsDMARDs therapy and 416 patients with HBsAg-/HBcAb+ were enrolled. Factors associated with HBV reactivation were analysed. RESULTS: During 2845 person-years of follow-up, 27 of 416 (6.5%,9.5 per 1000 person-years) patients developed HBV reactivation, with a cumulative rate of HBV reactivation of 3.5% at 5 years, 6.1% at 10 years and 24.2% at 17 years. The median interval from beginning b/tsDMARDs to HBV reactivation was 85 months (range: 9-186 months). The risk of HBV reactivation varied by type of b/tsDMARD, with rituximab having the highest risk (incidence rate: 48.3 per 1000 person-years), followed by abatacept (incidence rate: 24.0 per 1000 person-years). In multivariate analysis, rituximab (adjusted hazard ratio [aHR]: 15.77, 95% confidence interval [CI]: 4.12-60.32, p = .001), abatacept (aHR: 9.30, 1.83-47.19, p = .007), adalimumab (aHR: 3.86, 1.05-14.26, p = .04) and negative baseline HBV surface antibody (anti-HBs, <10 mIU/mL) (aHR: 3.89, 1.70-8.92, p < .001) were independent risk factors for HBV reactivation. CONCLUSION: HBsAg-/HBcAb+ RA patients are susceptible to HBV reactivation during b/tsDMARD therapy. Those with negative baseline anti-HBs and those on certain b/tsDMARDs, such as rituximab, abatacept and adalimumab, have high reactivation risks. Risk stratification and management should be based on the patient's baseline anti-HBs titre and type of therapy.

Increased frequency of hospital admissions with active systemic lupus erythematosus disease activity defined by two different disease activity indices: A cohort study.

The objective of this cohort study was to evaluate the association between the frequency of hospital admissions and disease activity, as defined by two different disease activity measurements: the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) and the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), in adult patients with systemic lupus erythematosus (SLEs). Patients with SLE were recruited from the rheumatology outpatient department of a regional hospital in southern Taiwan. SLE-DAS and SLEDAI-2K were used to define SLE disease activity and the cause of hospital admissions was identified by a rheumatologist based on medical records. A generalized linear model (GLM) with gamma distribution and log-linked function was used to analyze variables associated with the frequency of admission. The mean frequency of hospitalization was 0.34 times per year for all-cause and 0.21 times per year for SLE-related admission. Multivariate GLM analysis showed that moderate/severe SLE disease activity defined by SLE-DAS was associated with an increased frequency of all-cause and SLE-related hospital admissions while adjusting for other covariates. Moderate/severe SLE disease activity defined by SLEDAI-2K was only significantly associated with an increased frequency of all-cause hospitalization. When steroid dosage was included in the model, moderate/severe SLE disease activity defined by the SLE-DAS remained significantly associated with SLE-related hospital admissions (p = 0.032). In conclusion, disease activity defined by the SLE-DAS, but not SLEDAI-2K was associated with an increased frequency of SLE-related hospitalization. Steroid dosage, a lower educational level, and smoking were associated with an increased frequency of hospital admissions, whereas underweight and alcohol use were associated with a decreased frequency of hospital admissions. Rheumatologists should promptly control SLE disease activity of their patients, provide them with adequate health education, and maintain steroid doses to as low as possible to reduce the risk of hospital admissions.

Increased risk of hospital admissions in patients with active systemic lupus erythematosus (SLE) classified according to two different SLE disease activity indices: a prospective cohort study.

OBJECTIVES: The aim of this prospective cohort study was to investigate the risk of hospital admissions within one year in patients with active systemic lupus erythematosus (SLE), classified according to the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) or the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K). METHODS: This study was conducted in adult patients with SLE recruited from the rheumatology outpatient department in a regional hospital in southern Taiwan. SLE disease activity was measured with SLE-DAS and SLEDAI-2K. The computerised patient record database was accessed to identify patients' hospital admissions. Cox regression analyses were used to estimate the hazard ratio (HR) for all-cause and SLE-related hospital admission in SLE patients classified by SLE-DAS and SLEDAI-2K. RESULTS: A total of 326 adult patients with SLE completed this study. All-cause and SLE-related hospital admissions within one year occurred in 17.5% and 12.6% of the patients, respectively. Results of the Cox regression analysis indicated that SLE patients with moderate/severe disease activity classified by the SLE-DAS (HR=2.43, p=0.005) but not moderate/severe disease activity classified by the SLEDAI-2K (HR=1.84, p=0.057) was significantly associated with the risk of SLE-related admissions. However, only moderate/severe disease activity classified by the SLE-DAS was significantly associated with the risk of all-cause admissions (HR=1.94, p=0.016). When steroid dosage was considered, only the steroid dosage was significantly associated all-cause and SLE-related admissions. CONCLUSIONS: In this study, SLE disease activity classified by SLE-DAS was significantly associated with an increased risk for both all-cause and SLE-related hospital admissions. Rheumatologists should be vigilant for increased risk of hospital admissions in patients with moderate/high SLE disease activity as classified by SLE-DAS.

Increased Expression of Long Noncoding RNA LOC100506314 in T cells from Patients with Nonsegmental Vitiligo and Its Contribution to Vitiligo Pathogenesis.

This study aimed to identify the abnormal expression of long noncoding RNAs (lncRNAs) in T cells from patients with vitiligo and to investigate their functional roles in the immune system. Using microarray analysis, the expression levels of RNA transcripts in T cells from patients with vitiligo and controls were compared. We identified several genes and validated their expression levels in T cells from 41 vitiligo patients and 41 controls. The biological functions of the lncRNAs were studied in a transfection study using an RNA pull-down assay, followed by proteomic analysis and western blotting. The expression levels of 134 genes were significantly increased, and those of 142 genes were significantly decreased in T cells from vitiligo patients. After validation, six genes had increased expression, and three genes had decreased expression in T cells from patients with vitiligo. T-cell expression of LOC100506314 was increased in vitiligo, especially CD4+, but not CD8+ T cells. The expression levels of LOC100506314 in CD4+ T cells was positively and significantly associated with the severity of vitiligo. LOC100506314 was bound to the signal transducer and activator of transcription 3 (STAT3) and macrophage migration inhibitory factor (MIF). Enhanced expression of LOC100506314 inhibited the phosphorylation of STAT3, protein kinase B (AKT), and extracellular signal-regulated protein kinases (ERK), as well as the levels of nuclear protein of p65 and the expression of IL-6 and IL-17 in Jurkat cells and T cells from patients with vitiligo. In conclusion, this study showed that the expression of LOC100506314 was elevated in CD4+ T cells from patients with vitiligo and associated the severity of vitiligo. LOC100506314 interacted with STAT3 and MIF and inhibited IL-6 and IL-17 expression by suppressing the STAT3, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), AKT, and ERK pathways. Enhanced expression of LOC100506314 in T cells may be a potential treatment strategy for vitiligo.

Effects of a walking exercise programme on disease activity, sleep quality, and quality of life in systemic lupus erythematosus patients.

AIM: This quasi-experimental study aimed to explore effects of walking exercise on disease activity, sleep quality, and quality of life among individuals with systemic lupus erythematosus. METHODS: After recruiting people with systemic lupus erythematosus from a hospital in Taiwan between October 2020 and June 2021, participants were free to opt to receive one walking exercise programme plus standard care for 3 months or to membership of a control group receiving routine care. Primary outcomes included Systemic Lupus Erythematosus Disease Activity Score, the Pittsburgh Sleep Quality Scale, and a quality-of-life scale for patients with systemic lupus erythematosus, namely, LupusQoL. These scales were administered first, at baseline and later, within 1 week following completion of the intervention. Between-group effects were compared using generalized estimating equations with adjustment for baseline variables. RESULTS: The experimental and control groups each included 40 participants. Multivariate analysis indicated that adding the walking exercise programme into routine care elevated sleep quality and LupusQoL (the latter in the subscales of physical health, planning, and intimate relationships), except for disease activity. CONCLUSION: Findings of this study supported the addition of walking exercise as part of routine care for people with systemic lupus erythematosus and may be a reference in the provision of adequate care for these patients.

Rheumatic Diseases: New Progress in Clinical Research and Pathogenesis.

Rheumatic diseases encompass a group of disorders that primarily target the musculoskeletal system, including joints, bones, muscles, and connective tissue [...].

Performance of a New Instrument for the Measurement of Systemic Lupus Erythematosus Disease Activity: The SLE-DAS.

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease that affects multiple organ systems and manifests in a relapsing-remitting pattern. Consequently, it is paramount for rheumatologists to assess disease activity, identify flare-ups, and establish treatment goals for patients with SLE. In 2019, the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) was introduced as a novel tool for measuring disease activity. This tool refines the parameters of the established SLE Disease Activity Index 2000 (SLEDAI-2K) to enhance the assessment process. This review aims to provide an introduction to the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) and summarizes research on its development, its comparison with existing disease activity measures, and its performance in clinical settings. Literature searches on PubMed using the keyword "SLE-DAS" were conducted, covering publications from March 2019 to September 2023. Studies that compared SLE-DAS with other SLE disease activity measurement tools were reviewed. Findings indicated that SLE-DAS consistently performs on par with, and sometimes better than, traditional measures in assessing clinically meaningful changes, patient improvement, disease activity, health-related quality of life, hospitalization rates, and disease flare-ups. The association between SLE-DAS and mortality rates among patients with SLE, however, remains to be further explored. Although SLE-DAS is a promising and potentially effective tool for measuring SLE disease activity, additional research is needed to confirm its effectiveness and broaden its clinical use.

Relationship between Chinese Herbal Medicine Use and Risk of Sjögren's Syndrome in Patients with Rheumatoid Arthritis: A Retrospective, Population-Based, Nested Case-Control Study.

Background and Objectives: Sjögren's Syndrome (SS) is a common extra-articular feature among subjects with rheumatoid arthritis (RA). While Chinese herbal medicine (CHM) has been used to treat symptoms of RA for many years, few studies have examined its efficacy in guarding against the SS onset. This study aimed to compare risk of SS for RA patients with and without use of CHM. Materials and Methods: Data obtained for this nested case-control study were retrieved from Taiwanese nationwide insurance database from 2000-2013. Cases with SS claims were defined and matched to two randomly selected controls without SS from the recruited RA cohorts. Risk of SS in relation to CHM use was estimated by fitting multiple conditional logistic regression. Results: Patients aged between 20 and 80 years were included and 916 patients with incident SS were matched to 1832 non-SS controls by age, sex and index year. Among them, 28.1% and 48.4% cases ever received CHM therapy, respectively. After adjusting for baseline characteristics, CHM use was found to be related to a lower risk of SS among them (adjusted odds ratio = 0.40, 95% confidence interval: 0.34-0.47). A dose-dependent, reverse association, was further detected between the cumulative duration of CHM use and SS risk. Those receiving CHM therapy for more than 730 days showed a significantly reduced risk of SS by 83%. Conclusions: Findings of this study indicated that the add-on CHM formula, as part of RA care, may be a beneficial treatment for prevention against the incident SS.

Brain-Derived Neurotrophic Factor Suppressed Proinflammatory Cytokines Secretion and Enhanced MicroRNA(miR)-3168 Expression in Macrophages.

We investigated the role of brain-derived neurotrophic factor (BDNF) and its signaling pathway in the proinflammatory cytokines production of macrophages. The effects of different concentrations of BDNF on proinflammatory cytokines expression and secretion in U937 cell-differentiated macrophages, and human monocyte-derived macrophages were analyzed using enzyme-linked immunosorbent assay and real-time polymerase chain reaction. The CRISPR-Cas9 system was used to knockout p75 neurotrophin receptor (p75NTR), one of the BDNF receptors. Next-generation sequencing (NGS) was conducted to search for BDNF-regulated microRNA. A very low concentration of BDNF (1 ng/mL) could suppress the secretion of interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and IL-6 in lipopolysaccharide (LPS)-stimulated macrophages but did not change their mRNA expression. BDNF suppressed IL-1ß and IL-6 secretion in human monocyte-derived macrophages. In U937 cells, BDNF suppressed the phosphorylation of JNK and c-Jun. The p75NTR knockout strongly suppressed IL-1ß, IL-6, and TNF-α secretion in macrophages and LPS-stimulated macrophages. BDNF regulated the expression of miR-3168 with Ras-related protein Rab-11A as its target. In conclusion, BDNF suppressed proinflammatory cytokines secretion in macrophages and inhibited the phosphorylation of JNK. Knockout of p75NTR suppressed proinflammatory cytokines expression and secretion. BDNF upregulated the expression of miR-3168. The inhibition of p75NTR could be a potential strategy to control inflammation.

Increased dental visits in patients with rheumatoid arthritis: a secondary cohort analysis of population based claims data.

OBJECTIVE: To study the utilization of dental care in patients with rheumatoid arthritis (RA) and compare the incidence of common dental disorders in patients with and without RA. METHODS: This data used in this study was from the population-based Taiwan's National Health Insurance Research Database. We identified 1337 patients with newly diagnosed RA between January 2000 and December 2012. We also identified 13,370 individual without a diagnosis of RA using frequency matching on 5-year age intervals, sex, and index year. Patients with a diagnosis of primary Sjögren's syndrome were excluded. Dental disorders were identified using respective ICD-9-CM codes confirmed by dentists. The incidence and incidence rate ratio [IRR] of each dental disorders were calculated using Poisson regression. RESULTS: Compared with the comparison cohort, the prevalence of dentist visits in the RA cohort were significantly higher (70.3% vs. 66.7%, p = 0.008) and the frequency of dentist visits in the RA cohort were also significantly higher (median 2.67 vs. 1.78 per year, p < 0.001). In addition, the incidence of visits for dental caries (adjusted IRR 1.16, p < 0.001), pulpitis (adjusted IRR 1.12, p = 0.044), gingivitis (adjusted IRR 1.13, p = 0.027), periodontitis (adjusted IRR 1.13, p = 0.004), and oral ulcer (adjusted IRR 1.24, p = 0.003) were higher in patients with RA. CONCLUSIONS: An elevated prevalence and frequency of dental visits were associated with patients with RA. In addition, elevated incidence of dental disorders, including dental caries, pulpitis, gingivitis, periodontitis, and oral ulceration, were observed. Oral health should be accessed regularly in patients with RA.

Increased Risk of Common Orthopedic Surgeries for Patients with Rheumatic Diseases in Taiwan.

Background and Objectives: Rheumatic diseases, including rheumatoid arthritis, ankylosing spondylitis, psoriasis, and systemic lupus erythematosus (SLE), are characterized by chronic arthritis or spondyloarthritis, which can lead to joint and spine destruction. Our previous studies showed that the risk of common orthopedic surgeries, including total knee replacement (TKR), total hip replacement (THR), or spine surgery, was increased in patients with rheumatoid arthritis, ankylosing spondylitis, psoriasis, and SLE. The aim of this review was to summarize the risk of TKR, THR, cervical spine, and lumbar spine surgery on the basis of studies conducted using data from Taiwan's National Health Insurance Research Database (NHIRD). Materials and Methods: The risk of TKR, THR, cervical spine surgery, and lumbar spine surgery in patients with rheumatoid arthritis, ankylosing spondylitis, psoriasis, and SLE was summarized from the results of our previous studies and unpublished findings based on NHIRD data. Results: Patients with rheumatoid arthritis and psoriasis and men with ankylosing spondylitis showed an increased risk of TKR. Patients with rheumatoid arthritis, ankylosing spondylitis, and women with SLE showed an increased risk of receiving THR. Only patients with ankylosing spondylitis had an increased risk of cervical spine surgery, and patients with rheumatoid arthritis or ankylosing spondylitis showed an increased risk of lumbar spine surgery. Although the risk of THR, TKR, or spine surgery in these patients has declined in the era of biologics use, direct evidence for the effects of biologics agents is not yet available. Conclusions: There was an increased risk of common orthopedic surgery in patients with rheumatoid arthritis, ankylosing spondylitis, psoriasis, and SLE. Clinicians should be vigilant to reduce the increased risk of TKR and THR in young and middle-aged patients with rheumatoid arthritis, THR in young patients with ankylosing spondylitis, and young female patients with SLE, as well as cervical spine surgery in young patients with ankylosing spondylitis.

Risk of Spine Surgery in Patients with Rheumatoid Arthritis: A Secondary Cohort Analysis of a Nationwide, Population-Based Health Claim Database.

Background and Objectives: To study the risk of spine surgery, including cervical and lumbar spine surgeries in patients with rheumatoid arthritis (RA) compared with those without a diagnosis of RA. Materials and Methods: This is a secondary data analysis using population-based health claim data. We identified newly diagnosed adult patients with RA between January 2000 and December 2012, according to the International Classification of Diseases, Ninth revision, clinical modification code 714.0 from Taiwan's National Health Insurance Research Database. Using data frequency-matched by 10-year age intervals, sex and index year with the RA cohort at a ratio of 5:1, we assembled a comparison cohort. All patients were followed until the study outcomes occurred (overall spine surgery, cervical spine surgery, or lumbar spine surgery) or the end of follow-up. Adjusted incidence rate ratios (aIRR) were calculated using Poisson regression analysis with age group, socioeconomic status, geographical region, and osteoporosis included as potential confounders. Results: We identified 1287 patients with RA and 6435 patients without RA. The incidence of overall spine surgery (aIRR = 2.13, 95% confidence interval (CI) = 1.49-3.04) and lumbar spine surgery (aIRR = 2.14, 95% CI = 1.46-3.15) were all significantly higher in the RA cohort. Moreover, females over 45 years of age were particularly at risk for lumbar spine surgery. In RA patients, older age and the combination with the diagnosis of osteoporosis had an elevated risk for overall and lumbar spine surgery. Conclusion: Patients with RA had an increased risk of receiving spine surgery. Physicians should be vigilant for possible spinal problems in women and older patients with RA.

Association of Clinical Manifestations of Systemic Lupus Erythematosus and Complementary Therapy Use in Taiwanese Female Patients: A Cross-Sectional Study.

Background and Objectives: Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease that affects predominantly women in the childbearing years. Patients may seek complementary therapies to manage their health and to reduce symptoms. However, to our knowledge, no studies have explored the association between clinical manifestations of SLE and complementary therapies. Therefore, this study aimed to investigate the association of complementary therapies with common clinical manifestations in Taiwanese female patients with SLE. Materials and Methods: A cross-sectional study was conducted at a regional teaching hospital in southern Taiwan. Outpatients from the rheumatology clinic who met the inclusion criteria were consecutively recruited. Demographic data, clinical manifestations of SLE, and types of complementary therapy use were determined using paper-based questionnaire. Multiple logistic regression analyses were conducted to investigate the use of complementary therapies associated with clinical manifestations of SLE. Results: Of the 317 female patients with SLE, 60.9% were 40 years or older. The five SLE clinical manifestations with the highest prevalence were Raynaud's phenomenon (61.2%), photosensitivity (50.2%), Sjögren's syndrome (28.4%), arthralgia and arthritis (22.1%), and renal involvement (14.5%). Multiple logistic regression analyses revealed that Raynaud's phenomenon was significantly associated with fitness walking or strolling (adjusted odds ratio [aOR] 1.77; p = 0.027) and fish oil supplements (aOR 3.55, p < 0.001). Photosensitivity was significantly and inversely associated with the use of probiotics (aOR 0.49; p = 0.019). Renal involvement was significantly associated with the use of probiotics (aOR 2.43; p = 0.026) and visit to the Chinese medicine department in a hospital (aOR 3.14, p = 0.026). Conclusions: We found that different clinical manifestations of SLE were associated with the use of different complementary therapies. Health care providers should have up-to-date knowledge of common complementary therapies and be ready to provide evidence-based advice to patients with SLE.

HLA-B*27 Heavy Chain Homo-Oligomers Promote the Cytotoxicity of NK Cells via Activation of PI3K/AKT Signaling.

Background and Objectives: Ankylosing spondylitis (AS) is a chronic inflammatory disease and is highly linked with the expression of the human leukocytic antigen-B*27 (HLA-B*27) genotype. HLA-B*27 heavy chain (B*27-HC) has an innate characteristic to slowly fold, resulting in the accumulation of the misfolded B*27-HC and the formation of homo-oligomeric B*27-HC molecules. The homo-oligomeric B*27-HC can act as a ligand of KIR3DL2. Interaction of the homo-oligomeric B*27-HC molecules with KIR3DL2 will trigger the survival and activation of KIR3DL2-positive NK cells. However, the effects of homo-oligomeric B*27-HC molecules associated with KIR3DL2 on the cytotoxic activity of NK cells and their cytokine expressions remain unknown. Materials and Methods: HLA-B*-2704-HC was overexpressed in the HMy2.C1R (C1R) cell line. Western blotting and quantitative RT-PCR were used to analyze the protein expression and cytokine expression, respectively, when C1R-B*-2704 cells that overexpress B*2704-HC were co-cultured with NK-92MI cells. Flow cytometry was used to analyze the cytotoxicity mediated by NK-92MI cells. Results: Our results revealed that NK-92MI cells up-regulated the expression of perforin and enhanced the cytotoxic activity via augmentation of PI3K/AKT signaling after co-culturing with C1R-B*2704 cells. Suppression of the dimerized B*27-HC formation or treatment with an inhibitor of PI3K, LY294002, or with an anti-B*27-HC monoclonal antibody can reduce the perforin expression of NK-92MI after co-culturing with C1R-B*-2704. Co-culturing with C1R-B*-2704 cells suppressed the TNF-α and IL6 expressions of NK-92MI cells. Conclusion: Stimulation of NK cell-mediated cytotoxicity by homo-oligomeric B*27-HC molecules may contribute to the pathogenesis of AS.

Risk of Hepatitis B Virus Reactivation in Rheumatoid Arthritis Patients Undergoing Tocilizumab-Containing Treatment.

BACKGROUND AND AIM: To investigate the risk of hepatitis B virus reactivation in patients undergoing long-term tocilizumab therapy for rheumatoid arthritis. METHOD: From January 2011 through August 2019, a total of 97 patients were enrolled in this retrospective study. Clinical data, comedications, and the occurrence of HBV reactivation were recorded. RESULTS: Seven patients were HBsAg+ (7.2%), 64 were HBsAg-/HBcAb+ (65.9%), and 26 were HBsAg-/HBcAb- (26.8%). The median disease follow-up time was 9 years. TCZ was administered for a median of 29 months. Four patients (4.1%) experienced HBV reactivation after tocilizumab therapy. Of the 7 HBsAg+ patients, 4 received antiviral prophylaxis and had no HBV reactivation; the remaining 3 patients did not receive antiviral prophylaxis, and all 3 (100%) experienced HBV reactivation and hepatitis flare-up. Hyperbilirubinemia occurred in 2 of these 3 patients, with mild prothrombin time prolongation in one. After salvage entecavir treatment, all patients had a favorable outcome. Of the 64 HBsAg-/HBcAb+ patients, only one became positive for serum HBV DNA (2.5 × 107 IU/mL) after 18 months of tocilizumab treatment (1.6%; 1/64). This patient was immediately treated with entecavir, which prevented hepatitis flare-up. CONCLUSIONS: Tocilizumab is widely used in treating rheumatoid arthritis and has the potential to reduce the mortality rate among severe COVID-19 patients. However, HBV reactivation needs to be considered. HBsAg+ patients have a high risk of HBV reactivation, which could be prevented by antiviral prophylaxis. Although the risk of reactivation is low in HBsAg-/HBcAb+ patients, strict monitoring is necessary.

Increased Serum Levels of Brain-Derived Neurotrophic Factor Contribute to Inflammatory Responses in Patients with Rheumatoid Arthritis.

The aim of this study is to investigate the role of brain-derived neurotrophic factor (BDNF) in the inflammatory responses in patients with rheumatoid arthritis (RA). Serum levels of BDNF and the precursor form of BDNF (proBDNF) from 625 RA patients and 40 controls were analyzed using enzyme-linked immunosorbent assay. Effects of BDNF on the mitogen-activated protein kinase pathway were analyzed by Western blotting. Microarray analysis was conducted to search BDNF regulated gene expression in Jurkat cells, and the differentially expressed genes were validated using T cells from patients with RA and controls. Serum BDNF levels were significantly elevated in patients with RA compared with the controls. Low serum BDNF levels were found in RA patients with anxiety or receiving biologics treatment. BDNF (20 ng/mL) enhanced the phosphorylation of ERK, JNK, and c-Jun, but suppressed the phosphorylation of p38, whereas BDNF (200 ng/mL) enhanced the phosphorylation of ERK and p38. After validation, the expression of CAMK2A, MASP2, GNG13, and MUC5AC, regulated by BDNF and one of its receptors, NGFR, was increased in RA T cells. BDNF increased the IL-2, IL-17, and IFN-γ expression in Jurkat cells and IL-2 and IFN-γ secretion in activated peripheral blood mononuclear cells.

Identification of phostensin in association with Eps 15 homology domain-containing protein 1 (EHD1) and EHD4.

Phostensin (PTS) encoded by KIAA1949 is a protein phosphatase 1 (PP1)-binding protein. In order to explore the cellular functions of PTS, we have searched PTS-binding proteins by using co-immunoprecipitation in combination with shotgun proteomics. Here, we report two novel PTS-binding proteins, Eps 15 homology domain-containing protein 1 (EHD1) and EHD4. PTS associated with EHD proteins was also observed in GST pull-down assays. Immunofluorescence microscopy demonstrated that the complex was co-localized at the endocytic vesicles. EHD proteins have been known to play a critical role in regulation of endocytic transport. Overexpression of PTS-ß can attenuate the endocytic trafficking of transferrin.

Risks of ophthalmic disorders in patients with systemic lupus erythematosus - a secondary cohort analysis of population-based claims data.

BACKGROUND: Systemic lupus erythematosus (SLE) can directly affect various part of the ocular system, but there was no comprehensive analysis of ophthalmic disorders of patients with SLE using population-based data. The aim of this study was to investigate the frequency and prevalence of ophthalmic disorders for ophthalmologist visits in adult patients with SLE and to evaluate the risk of dry eye syndrome, cataracts, glaucoma, episcleritis and scleritis, and retinal vascular occlusion in these patients. METHODS: The Taiwan's National Health Insurance Research Database was used to assemble a SLE cohort consisting of newly diagnosed SLE between 2000 and 2012. A comparison cohort was also sampled from the same database and it consisted of 10 patients without SLE for each patient with SLE, based on frequency matching for sex, five-year age interval, and index year. Both cohorts were followed until either the study outcomes have occurred or the end of the follow-up period. RESULTS: Patients with SLE (n = 521) exhibited a significantly higher prevalence (68.1% vs. 60.5%, P = 0.001) and frequency (median 5.51 vs. 1.71 per 10 years, P <  0.001) for outpatient ophthalmologist visits compared with patients without SLE. The risk of dry eye syndrome (adjusted incidence rate ratio [IRR] 4.45, P <  0.001), cataracts (adjusted IRR 3.18, P <  0.001), and glaucoma (adjusted IRR 2.23, P = 0.002) were significantly higher in patients with SLE. In addition, the risk of several SLE related ophthalmic disorders, including episcleritis and scleritis (adjusted IRR 6.11, P <  0.001) and retinal vascular occlusion (adjusted IRR 3.81, P = 0.023) were significantly higher in patients with SLE. CONCLUSIONS: The increased risk of dry eye syndrome, cataracts, glaucoma, episcleritis and scleritis, and retinal vascular occlusion in patients with SLE deserves vigilance.

The effectiveness of nurse-led case management for patients with rheumatoid arthritis in Taiwan.

BACKGROUND: Case management is a patient-centred approach which has shown efficacy in managing patients with chronic and life-threatening disease. Presently, the effect of case management delivered by nurses for rheumatoid arthritis (RA) patients remains unclear, especially for those subjects who reside in Asia. This study aimed to examine the effectiveness of nurse-led case management (NLCM) among RA patients in Taiwan. METHODS: A quasi-experimental research design was utilised to recruit RA patients from a hospital in Taiwan. All patients who were diagnosed as having RA from January 2017 to June 2018 were free to opt to participate in the intervention. The experiment group (n = 50) received six sessions of NLCM over six months, while the control group (n = 46) received only standard care during the same time period. Effectiveness data were collected through the review of medical records and a structured questionnaire that included the Taiwanese Depression Questionnaire (TDQ), the arthritis self-efficacy scale and a disease activity score by 28 joints (DAS28) at three time points (T1: before NLCM; T2: three days after NLCM completion; and T3: six months after NLCM completion). The effects of NLCM were determined using a generalised estimating equations model. RESULTS: After adjusting for several potential confounders, we found that the NLCM implementation decreased the levels of DAS28 (T1 = -0.78; T2 = -0.85; all at P = .01) and TDQ (T1 = -3.86; T2 = -10.57; all at P < .05) and enhanced ASES level for RA patients (T1 = 132.03; T2 = 484.69; all at P < .05). CONCLUSIONS: This study adopted a non-randomised, unblinded and uncontrolled intervention, and the findings supported the positive effects of NLCM following the use of a robust statistical method. The findings may serve as a reference for instituting more appropriate interventions for RA patients.

The Essential Role of Peptidylarginine Deiminases 2 for Cytokines Secretion, Apoptosis, and Cell Adhesion in Macrophage.

OBJECTIVE: The study aims to investigate the functional roles of peptidylarginine deiminase 2 (PADI2) in macrophages. METHODS: The clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein-9 nuclease (Cas9) system was used to knockout PADI2 in U937 cells. U937 cells were introduced to differentiate macrophages and were stimulated with lipopolysaccharides (LPS). The protein expression of PADI2, PADI4, and citrullinated proteins were analyzed by Western blotting. The mRNA and protein levels of interleukin 1 beta (IL-1ß), IL-6, and tumor necrosis factor-alpha (TNF-α) were analyzed using RT-PCR and ELISA, respectively. Cell apoptosis was analyzed using flow cytometry. Cell adhesion assay was performed using a commercially available fibrinogen-coated plate. RESULTS: PADI2 knockout could markedly suppress the PADI2 protein expression, but not the PADI4 protein expression. PADI2 knockout decreased the protein levels of citrullinated nuclear factor κB (NF-κB) p65, but not those of citrullinated histone 3, resulting in the decreased mRNA expression levels of IL-1ß and TNF-α in the U937 cells and IL-1ß and IL-6 in the differentiated macrophages and the macrophages stimulated with LPS. The cytokines levels of IL-1ß, IL-6, and TNF-α were all dramatically decreased in the PADI2 knockout group compared with in the controls. PADI2 knockout prevented macrophages apoptosis via the decreased caspase-3, caspase-2, and caspase-9 activation. PADI2 knockout also impaired macrophages adhesion capacity through the decreased protein levels of focal adhesion kinase (FAK), phospho-FAK, paxillin, phospho-paxillin, and p21-activated kinase 1. CONCLUSION: This study showed that PADI2 could promote IL-1ß, IL-6, and TNF-α production in macrophages, promote macrophage apoptosis through caspase-3, caspase-2, and caspase-9 activation and enhance cell adhesion via FAK, paxillin, and PAK1. Therefore, targeting PADI2 could be used as a novel strategy for controlling inflammation caused by macrophages.