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.

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.

Consensus recommendations on managing the selected comorbidities including cardiovascular disease, osteoporosis, and interstitial lung disease in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA)-related comorbidities, including cardiovascular disease (CVD), osteoporosis (OP), and interstitial lung disease (ILD), are sub-optimally managed. RA-related comorbidities affect disease control and lead to impairment in quality of life. We aimed to develop consensus recommendations for managing RA-related comorbidities. METHODS: The consensus statements were formulated based on emerging evidence during a face-to-face meeting of Taiwan rheumatology experts and modified through three-round Delphi exercises. The quality of evidence and strength of recommendation of each statement were graded after a literature review, followed by voting for agreement. Through a review of English-language literature, we focused on the existing evidence of management of RA-related comorbidities. RESULTS: Based on experts' consensus, eleven recommendations were developed. CVD risk should be assessed in patients at RA diagnosis, once every 5 years, and at changes in DMARDs therapy. Considering the detrimental effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids on CVD risks, we recommend using the lowest possible dose of corticosteroids and prescribing NSAIDs cautiously. The OP/fragility fracture risk assessment includes dual-energy X-ray absorptiometry and fracture risk assessment (FRAX) in RA. The FRAX-based approach with intervention threshold is a useful strategy for managing OP. RA-ILD assessment includes risk factors, pulmonary function tests, HRCT imaging and a multidisciplinary decision approach to determine RA-ILD severity. A treat-to-target strategy would limit RA-related comorbidities. CONCLUSIONS: These consensus statements emphasize that adequate control of disease activity and the risk factors are needed for managing RA-related comorbidities, and may provide useful recommendations for rheumatologists on managing RA-related comorbidities.

Association between clinical phenotypes of dermatomyositis and polymyositis with myositis-specific antibodies and overlap systemic autoimmune diseases.

ABSTRACT: The aim of this study was to evaluate the association between clinical phenotypes of dermatomyositis (DM) and polymyositis (PM) with myositis-specific antibodies (MSAs), and overlap diagnosis of systemic autoimmune diseases.This cross-sectional study was conducted on 67 patients with DM and 27 patients with PM recruited from a regional hospital in southern Taiwan. Clinical phenotypes of DM and PM were assessed and MSAs were measured using a commercial line blot assay. The association of clinical phenotypes of DM and PM with MSAs and overlap diagnosis of systemic autoimmune diseases was performed using univariate and multiple logistic regression analyses.Clinically, patients with DM and PM and overlap diagnosis of systemic sclerosis were associated with a higher risk of interstitial lung diseases (ILDs) (odds ratio [OR] = 6.73; P = .048), Raynaud phenomenon (OR = 7.30; P = .034), and malignancy (OR = 350.77; P = .013). The risk of malignancy was also associated with older age (OR 1.31; P = .012), and male patients were associated with a higher risk of fever. For MSAs, anti-aminoacyl-tRNA synthetase antibodies were associated with ILD, antinuclear antibody were associated with a lower risk of arthritis, anti-transcription intermediary factor 1-gamma antibodies were associated with milder symptoms of muscle weakness, anti-Ku antibodies were associated with overlap diagnosis of systemic lupus erythematosus, and anti-Ro52 antibodies were associated with the development of Raynaud phenomenon and Sjögren syndrome.MSAs and overlap diagnosis of systemic sclerosis were significantly associated with clinical phenotypes of DM and PM. Physicians should be vigilant for malignancy in older DM and PM patients with overlap diagnosis of systeic sclerosis. The possibility of developing ILD in patients with overlap diagnosis of systemic sclerosis or serum positivity of anti-aminoacyl-tRNA synthetase antibodies should be considered.

Reactivation of hepatitis B virus infection in patients with rheumatoid arthritis receiving tofacitinib.

OBJECTIVES: The aim of this study was to investigate hepatitis B virus (HBV) reactivation in patients with rheumatoid arthritis (RA) receiving tofacitinib. METHOD: This was a retrospective study performed in a regional teaching hospital in southern Taiwan. During January 2017 and December 2020, patients with a clinician-confirmed diagnosis of RA using tofacitinib for at least 3 months were enrolled. Serum HBV DNA levels and serum alanine aminotransferase were followed up around every 3 to 6 months to assess HBV reactivation. RESULTS: A total of 98 patients with RA were enrolled, and eight were hepatitis B surface antigen positive (HBsAg+) (8.1%), 64 were HBsAg-negative (HBsAg-)/hepatitis B core antibody positive (HBcAb+) (65.3%). In the HBsAg+ patients, two patients received antiviral prophylaxis, and none of them had HBV reactivation or hepatitis flare-up. The HBV reactivation rate was 33.3% (2/6) in the HBsAg+ RA patient without antiviral prophylaxis. Among the HBsAg-/HBcAb+ patients, the HBV reactivation rate was 3.1% (2/64). The incidence rate of HBV reactivation was 153.8 per 1000 person-years for overall HBsAg+ patients and 250 per 1000 person-years after excluding patients receiving antiviral prophylaxis. The incidence rate was 11.2 per 1000 person-years for HBsAg-/HBcAb+ patients with RA receiving tofacitinib. CONCLUSION: Tofacitinib could induce HBV reactivation in both HBsAg+ and HBsAg-/HBcAb+ RA patients. HBsAg+ patients receiving tofacitinib have a high incidence rate of HBV reactivation, which could be prevented by antiviral prophylaxis. Although the risk of reactivation is low in HBsAg-/HBcAb+ patients, closely monitoring HBV DNA and alanine aminotransferase should be suggested.

Association of Traditional Chinese Medicine Body Constitution and Health-Related Quality of Life in Female Patients with Systemic Lupus Erythematosus: A Cross-Sectional Study.

BACKGROUND: Traditional Chinese medicine (TCM) body constitution has been studied in many diseases, but few have focused on systemic lupus erythematosus (SLE) and particularly their association with disease-specific quality of life (QoL). Therefore, the aim of this study was to investigate the association of TCM body constitution and QoL in female patients with SLE. METHODS: A cross-sectional study was conducted on adult female patients with a clinician-confirmed diagnosis of SLE in a regional hospital in Taiwan. TCM body constitution types were determined using the Constitution in Chinese Medicine Questionnaire (CCMQ). Disease-specific QoL of the participants was assessed using the LupusQoL. Multiple linear regression analyses were conducted to assess the associations between TCM body constitution types with the score of each of the eight domains of LupusQoL and between the numbers of multiple unbalanced body constitution types and score of each of the eight domains of LupusQoL. RESULTS: Of the 317 female patients with SLE, 22 (6.9%) were classified to have a gentleness balanced body constitution type. Among the remaining 295 patients with unbalanced body constitution types, Qi-deficiency was the most common (64.4%), followed by Yin-deficiency (57.6%). Multiple linear regression analyses showed that Qi-deficiency was significantly associated with the emotional, pain, and fatigue domains of the LupusQoL, whereas Yin-deficiency was significantly associated with the emotional and fatigue domains of the LupusQoL. In addition, all domains of the LupusQoL showed a general pattern of poorer QoL with increasing numbers of unbalanced body constitution types. CONCLUSIONS: Different TCM body constitution types were significantly associated with various domains of the LupusQoL. A high prevalence of multiple body constitution types in patients with SLE was observed. A consistent pattern of poorer LupusQoL with increasing numbers of unbalanced body constitution types was evident.

A Comparison of the Correlation of Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) with Health-Related Quality of Life.

BACKGROUND AND AIM: The aim of this study was to compare the correlation of a recently developed systemic lupus erythematosus disease activity score (SLE-DAS) with the SLE disease activity index 2000 (SLEDAI-2K) with the Lupus Quality of Life questionnaire (LupusQoL) in Taiwanese patients with SLE. METHODS: A cross-sectional study was conducted in a regional teaching hospital in Taiwan from April to August 2019. Adult patients with a clinician-confirmed diagnosis of SLE based on the 1997 American College of Rheumatology revised criteria or the 2012 Systemic Lupus International Collaborating Clinics Classification Criteria were recruited. SLE disease activity was measured with both SLEDAI-2K and SLE-DAS. Disease-specific quality of life was assessed using the LupusQoL. RESULTS: Of the 333 patients with SLE in this study, 90.4% were female and 40% were between the ages of 20 and 39 years. The median SLEDAI-2K score was 4.00 (interquartile range [IQR] 2.00-7.50) and the median SLE-DAS score was 2.08 (IQR 1.12-8.24) in our patients with SLE. After adjusting for sex and age intervals, both SLEDAI-2k and SLE-DAS were significantly and inversely associated with all eight domains of LupusQoL. The magnitudes of the mean absolute error, root mean square error, Akaike Information Criterion, Bayesian Information Criterion, and coefficient of determination were comparable between SLEDAI-2K and SLE-DAS. CONCLUSIONS: There were no clear differences in the use of SLE-DAS over SLEDAI-2K in assessing HRQoL in patients with SLE. We suggest that, in this aspect, both SLEDAI-2K and SLE-DAS are effective tools for measuring disease activity in patients with SLE.

Down-Regulation of LOC645166 in T Cells of Ankylosing Spondylitis Patients Promotes the NF-κB Signaling via Decreasingly Blocking Recruitment of the IKK Complex to K63-Linked Polyubiquitin Chains.

Ankylosing spondylitis (AS) is a chronic inflammatory disease that mainly affects the spine. AS is highly associated with the expression of HLA-B27. Up to 95% AS patients are HLA-B27-positive. However, only 1%-2% of the HLA-B27-positive carriers suffer from AS, implying that other factors may also govern the development of AS. Long non-coding RNAs (lncRNAs) can regulate the immune response via their binding proteins. In the present study, we have identified that the levels of lncRNA, LOC645166, in T cells of AS patients were reduced. Overexpression of LOC645166 in Jurkat cells down-regulated the IL-23p19 expression and suppressed the JAK2/STAT3 signaling in response to stimulation by phorbol 12-myristate 13-acetate. Suppression of STAT3 activation by LOC645166 was also observed when Jurkat cells or T cells of AS patient were treated with anti-CD3/CD28 antibodies. In order to explore the role of LOC645166 in the pathogenesis of AS, RNA pull-down assay plus proteomic approach and western blotting were performed and identified that LOC645166 prefers binding the K63-linked polyubiquitin chains. LOC645166 can suppress recruitment of the IKK complex to K63-linked polyubiquitin chains and diminish IKK2 activation, leading to down-regulation of NF-κB activation. Down-regulation of LOC645166 expression in T cells of AS patients up-regulates NF-kB activation via decreasingly impeding recruitment of the IKK complex to K63-linked polyubiquitin chains, allowing AS patients to exhibit more sensitivity to stimulation by the proinflammatory cytokines or by TLR ligands.

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.

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.

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.

Risk factors, including different biologics, associated with depression and anxiety in patients with rheumatoid arthritis: a cross-sectional observational study.

BACKGROUND: To evaluate the associated factors of depression and anxiety in patients with rheumatoid arthritis (RA) and examine the effect of different biologics. METHODS: This cross-sectional study was conducted in a regional hospital in southern Taiwan from August of 2017 to April of 2018. A total of 625 patients with RA were included. RA disease activity was measured with Disease Activity Score over 28 joints based on erythrocyte sedimentation rate (DAS28-ESR). Depression and anxiety were measured with Hospital Anxiety and Depression Scale (HADS). RESULTS: Based on HADS scores, 38 subjects (6.1%) and 15 subjects (2.4%) were classified as depression and anxiety, respectively. Increased disease activity of RA is noted in RA patients with depression or anxiety, and among the items of DAS28-ESR, only the two subjective components: tender joint count over 28 joints (TJC28) and patient's global assessment (PGA) were significantly different. Multiple logistic regression analysis indicated that depression was significantly associated with TJC28 (adjusted odds ratio [aOR] = 1.10, 95% confidence interval [CI] 1.05-1.14) and female (aOR = 5.43, 95% CI 1.25-23.52); and anxiety was associated with TJC 28 (aOR = 1.07, 95% CI 1.00-1.15) and PGA (aOR = 1.03, 95% CI 1.01-1.06). Secondary analysis found a significantly lower risk of depression (aOR = 0.20, 95% CI 0.04-0.88) in patients receiving etanercept, but not anxiety, when compared with the non-biologic group. CONCLUSIONS: This study suggests that only subjective components of DAS28-ESR were significantly associated with depression and anxiety. In comparison with other biologics, patients receiving etanercept appeared to have a lower risk of depression.Key Points• Rheumatoid arthritis patients possessed higher risk of depression and anxiety.• Both depression and anxiety are strongly correlated with the subjective components of DAS28-ESR.• Etanercept might be the choice of biologics in rheumatoid arthritis patients with depression.

Factors associated with disease-specific quality of life in Taiwanese patients with ankylosing spondylitis: a cross-sectional study.

OBJECTIVE: The aim of this study was to assess the factors associated with disease-specific quality of life in Taiwanese patients with ankylosing spondylitis. DESIGN: A cross-sectional study. SETTING: A regional teaching hospital in southern Taiwan. PARTICIPANTS: Adult patients with ankylosing spondylitis recruited from the outpatient rheumatology clinics of the study hospital. PRIMARY OUTCOME MEASURE: Disease-specific quality of life assessed by the Evaluation of Ankylosing Spondylitis Quality of Life (EASi-QoL). RESULTS: Of the 265 patients, 57% were 20-49 years of age, with a male preponderance (75.5%). Multiple stepwise linear regression analysis indicated that a higher disease activity, assessed by the Ankylosing Spondylitis Disease Activity Score, was significantly and independently associated with a lower quality of life in all four domains (physical function, disease activity, emotional well-being and social participation) of the EASi-QoL. In addition, various independent factors, including educational level, nature of occupation, disease duration, dietary habit and body mass index, were significantly associated with different domains of the EASi-QoL. CONCLUSIONS: Our findings indicated that, in addition to disease activity and perceived health status, a number of other factors could significantly impact the different aspects of quality of life in patients with ankylosing spondylitis, which warrant special consideration and support from healthcare providers.

Increased peptidylarginine deiminases expression during the macrophage differentiation and participated inflammatory responses.

OBJECTIVE: To investigate the expression of peptidylarginine deiminases (PADIs) during macrophage differentiation and its role in inflammatory responses. METHODS: The protein expression of PADI2, PADI4, and citrullinated histone 3 in U937 cells, differentiated macrophages, and macrophages stimulated with lipopolysaccharides (LPS) were analyzed by Western blotting. Three PADI inhibitors were used for assessing their effects on the secretion of proinflammatory cytokines in macrophages. The differential expressed citrullinated proteins during macrophage differentiation were probed by self-prepared anti-citrullinated protein antibodies, and the reactive bands were sent for proteomic analyses. Transfection studies were conducted to search for the functions of specific proteins. A specific protein was cloned and citrullinated for its protein binding study. RESULTS: The expression of PADI2 and PADI4 markedly increased during macrophage differentiation, whereas the formation of citrullinated histone 3 increased after stimulated with lipopolysaccharides. Three PADI inhibitors suppressed the LPS mediated proinflammatory cytokines secretion, but did not affect the expression of PADI2 and PADI4. Plasminogen activator inhibitor-2 (PAI-2) was citrullinated during macrophage differentiation. The expression of PAI-2 increased during macrophage differentiation and further increased after stimulated with LPS. Suppressed PAI-2 expression decreased the expression and secretion of proinflammatory cytokines. Decreased PADI2 expression also suppressed the expression of PAI-2 and protein levels of citrullinated PAI-2. The citrullination of PAI-2 inhibited its binding ability to proteasome subunit beta type-1 (PSMB1). CONCLUSION: PADI2 and PADI4 protein levels increased during the macrophage differentiation resulting in protein citrullination, including PAI-2. The increased expression of PAI-2 promoted inflammatory response, and the citrullination of PAI-2 impaired its binding to PSMB1. Therefore, protein citrullination could play a critical role in macrophage differentiation and function.

Risks of hepatocellular carcinoma and cirrhosis-associated complications in patients with rheumatoid arthritis: a 10-year population-based cohort study in Taiwan.

BACKGROUND/PURPOSE: Although rheumatoid arthritis (RA) has been linked to several important malignancies, data for the risks of hepatocellular carcinoma (HCC) in patients with RA are scarce. We aimed to examine the risk of HCC and cirrhosis-associated complications and the use of biologics in a national representative RA sample in Taiwan. METHODS: All study subjects aged ≥ 18 years in the Taiwan National Health Insurance program between January 1, 2000, and December 31, 2009 were enrolled. We matched RA and non-RA subjects by propensity scores in a 1:1 ratio. Our primary outcome was a diagnosis of HCC and cirrhosis-associated complications during a 10-year follow-up period. The risk of outcomes was represented as a hazard ratio (HR) calculated in Cox proportional hazard regression models. RESULTS: 24,245 RA and 24,245 non-RA subjects were included in the primary outcome analysis. Mean overall person-years (PY) of follow-up were 116,608 PY for the RA cohort, and 234,280 PY for the non-RA cohort. The overall incidence of HCC and cirrhosis-associated complications was lower in the RA cohort than in the non-RA cohort (0.66% vs. 1.41% HCC events and 1.45% vs. 1.95% cirrhosis-associated complications events during 10-year follow-up). The HRs adjusted for age, sex, the frequency of medical visits, and CCI were 0.57 (0.46-0.71) for HCC and 0.67 (0.59-0.76) for HCC and cirrhosis-associated complications. Although immunomodulatory agents may alter the risk of malignancy, use of biologics did not increase HCC risk in RA patients. CONCLUSIONS: RA is associated with a reduced risk of developing HCC and cirrhosis-associated complications. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02880306.

Aberrant expression of interleukin-23-regulated miRNAs in T cells from patients with ankylosing spondylitis.

BACKGROUND: Interleukin (IL)-23 can facilitate the differentiation of IL-17-producing helper T cells (Th17). The IL-23/IL-17 axis is known to play a key role in the immunopathogenesis of ankylosing spondylitis (AS). We hypothesized that the expression of microRNAs (miRNAs, miRs) would be regulated by IL-23 and that these miRNAs could participate in the immunopathogenesis of AS. METHODS: Expression profiles of human miRNAs in K562 cells, cultured in the presence or absence of IL-23 for 3 days, were analyzed by microarray. Potentially aberrantly expressed miRNAs were validated using T-cell samples from 24 patients with AS and 16 control subjects. Next-generation sequencing (NGS) was conducted to search for gene expression and biological functions regulated by specific miRNAs in the IL-23-mediated signaling pathway. RESULTS: Initial analysis revealed that the expression levels of 12 miRNAs were significantly higher, whereas those of 4 miRNAs were significantly lower, in K562 cells after coculture with IL-23 for 3 days. Among these IL-23-regulated miRNAs, the expression levels of miR-29b-1-5p, miR-4449, miR-211-3p, miR-1914-3p, and miR-7114-5p were found to be higher in AS T cells. The transfection of miR-29b-1-5p mimic suppressed IL-23-mediated signal transducer and activator of transcription 3 (STAT3) phosphorylation in K562 cells. After NGS analysis and validation, we found that miR-29b-1-5p upregulated the expression of angiogenin, which was also upregulated in K562 cells after coculture with IL-23. Increased expression of miR-29b-1-5p or miR-211-3p could enhance interferon-γ expression. CONCLUSIONS: Among the miRNAs regulated by IL-23, expression levels of five miRNAs were increased in T cells from patients with AS. The transfection of miR-29b-1-5p mimic could inhibit the IL-23-mediated STAT3 phosphorylation and might play a role in negative feedback control in the immunopathogenesis of AS.

The role of aberrant expression of T cell miRNAs affected by TNF-α in the immunopathogenesis of rheumatoid arthritis.

BACKGROUND: Tumor necrosis factor-alpha (TNF-α) can cause diverse T cell dysfunctions in patients with rheumatoid arthritis (RA). It is involved in the regulation of microRNAs (miRNAs) expression in different cell types. We hypothesized that the expression of T cell miRNAs would be affected by TNF-α, and these miRNAs could participate in the immunopathogenesis of RA. METHODS: Expression profiles of 270 human miRNAs in Jurkat cells, cultured in the presence or absence of TNF-α for 7 days were analyzed by real-time polymerase chain reaction. Potentially aberrantly expressed miRNAs were validated using T cell samples from 35 patients with RA and 15 controls. Transfection studies were conducted to search for gene expression and biological functions regulated by specific miRNAs. RESULTS: Initial analysis revealed 12 miRNAs were significantly lower, whereas the expression level of miR-146a was significantly higher in Jurkat cells after being cultured with TNF-α for 7 days. Decreased expression of miR-139-3p, miR-204, miR-760, miR-524-5p, miR-136, miR-548d-3p, miR-214, miR-383, and miR-887 were noted in RA T cells. Expression levels of miR-139-3p, miR-204, miR-214, and miR-760 were correlated with the use of biologic agents. The transfection of miR-214 mimic suppressed TNF-α-mediated apoptosis of Jurkat cells. Increased phosphorylation of extracellular regulating kinase (ERK) and c-Jun N-terminal kinase (JNK) was noted in RA T cells and Jurkat cells after TNF-α exposure. Transfection of Jurkat cells with miR-214 mimic suppressed both the basal and TNF-α-mediated ERK and JNK phosphoryation. CONCLUSIONS: Among T cell miRNAs affected by TNF-α, the expression levels of nine miRNAs were decreased in T cells from patients with RA. The expression levels of miR-139-3p, miR-204, miR-214, and miR-760 increased in RA patients receiving biologic agents. The transfection of miR-214 reversed the TNF-α-mediated cells apoptosis and inhibited the phosphorylation of ERK and JNK in Jurkat cells.

Incident osteoarthritis and osteoarthritis-related joint replacement surgery in patients with ankylosing spondylitis: A secondary cohort analysis of a nationwide, population-based health claims database.

BACKGROUND: Ankylosing spondylitis (AS) might be associated with an increased risk of secondary osteoarthritis. However, there is a lack of studies assessing its impact on osteoarthritis-related surgery. The aim of this secondary cohort study was to investigate the risk of symptomatic osteoarthritis and osteoarthritis-related surgery, including total hip replacement surgery (THRS) and total knee replacement surgery (TKRS) in patients with AS. METHODS: Using the Taiwan's National Health Insurance Research Database, we identified 3,462 patients with AS between 2000 and 2012. A comparison cohort was assembled consisting of five patients without AS, based on frequency matching for sex, 10-year age interval, and index year, for each patient with AS. Both groups were followed until diagnosis of the study outcomes or the end of the follow-up period. RESULTS: Male patients with AS exhibited a significantly higher incidence of osteoarthritis (adjusted incidence rate ratio [IRR] 1.43; P < 0.001), THRS (adjusted IRR 12.59; P < 0.001), and TKRS (adjusted IRR 1.89; P = 0.036). Moreover, analyses stratified by age group (20-39 years versus 40-80 years) indicated a high IRR (adjusted IRR 27.66; P <0.001) for THRS among younger patients with AS. CONCLUSIONS: Male patients with AS had a significant higher risk of developing osteoarthritis, and receiving THRS and TKRS. Young patients with AS also showed a significant higher risk of receiving THRS.

Age-adjusted Charlson Comorbidity Index scores predict major adverse cardiovascular events and all-cause mortality among systemic lupus erythematosus patients.

OBJECTIVE: Cardiovascular events are the most frequent cause of death or disability among people with systemic lupus erythematosus (SLE). However, the causes of this increased the risk of major adverse cardiovascular events (MACEs) are not completely understood. The Age-adjusted Charlson Comorbidity Index (ACCI) is a prognostic classification that was initially developed for patients who have a number of comorbid conditions and the ACCI has been validated in many clinical settings. MATERIALS AND METHODS: In this study, 5998 patients were enrolled from the National Health Research Institute Database of Taiwan. All the patients' sequential clinical data related to their diagnosis of SLE were reviewed from 2004 to 2007 to determine their risk of MACE occurrence and of all-cause mortality using their ACCI scores. RESULTS: The predictive accuracy of the ACCI scores in relation to MACE occurrence among SLE patients was estimated and the C-statistic for this curve was found to be 0.687 (95% confidence interval [CI]: 0.664-0.709). The distribution of ACCI scores for MACE patients was 4.7%, 10.3%, 11.4%, and 21.5% for those with ACCI scores in the ranges of 0-1, 2-3, 4-5, and >6, respectively. A plot of the cumulative risk also showed a much higher risk among SLE patients with an ACCI score of >6. When patients were divided into different groups based on their ACCI scores, those with ACCI scores of >6 had an adjusted hazards ratio of 4.88 (95% CI: 3.84-6.19; P < 0.001) as compared to those with ACCI scores of 0-1. CONCLUSION: SLE patients with higher ACCI scores have a significantly higher risk of a MACE and of all-cause mortality. Our results suggested that ACCI scores may be useful as an index for estimating global cardiovascular risk among patients with SLE.