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.

Renal and survival benefits of seventeen prescribed Chinese herbal medicines against oxidative-inflammatory stress in systemic lupus erythematosus patients with chronic kidney disease: a real-world longitudinal study.

Background: Systemic lupus erythematosus (SLE) significantly links to LN, a type of CKD with high mortality despite modern Western treatments. About 70% of SLE patients develop LN, and 30% advance to end-stage renal disease (ESRD). Concerns about glucocorticoid side effects and LN worsening due to oxidative stress prompt alternative treatment searches. In Taiwan, over 85% of SLE patients opt for complementary methods, especially Chinese herbal medicine (CHM). We pinpointed seventeen CHMs for SLE (PRCHMSLE) with antioxidative and anti-inflammatory properties from national health insurance data (2000-2017). Our primary aim was to assess their impact on renal and survival outcomes in SLE patients progressing to CKD (SLE-CKD), with a secondary focus on the risks of hospitalization and hyperkalemia. Methods: We established a propensity-matched cohort of 1,188 patients with SLE-CKD, comprising 594 PRCHMSLE users and 594 nonusers. We employed Cox proportional hazards models and restricted mean survival time (RMST) analyses to assess the renal and survival outcomes of PRCHMSLE users. Moreover, we performed pooling and network analyses, specifically focusing on the renal effects linked to PRCHMSLE. Results: PRCHMSLE use was associated with decreased adjusted hazard ratios for ESRD (0.45; 95% confidence interval, 0.25-0.79, p = 0.006), all-cause mortality (0.56; 0.43-0.75, p < 0.0001), non-cardiovascular mortality (0.56; 0.42-0.75, p < 0.0001), and hospitalization (0.72; 0.52-0.96, p = 0.009). Hyperkalemia risk did not increase. Significant differences in RMST were observed: 0.57 years (95% confidence interval, 0.19-0.95, p = 0.004) for ESRD, 1.22 years (0.63-1.82, p < 0.0001) for all-cause mortality, and 1.21 years (0.62-1.80, p < 0.0001) for non-cardiovascular mortality, favoring PRCHMSLE use. Notably renoprotective PRCHMSLE included Gan-Lu-Ying, Anemarrhena asphodeloides Bunge [Asparagaceae; Rhizoma Anemarrhenae] (Zhi-Mu), Rehmannia glutinosa (Gaertn.) DC. [Orobanchaceae; Radix Rehmanniae] (Sheng-Di-Huang), Jia-Wei-Xiao-Yao-San, and Paeonia suffruticosa Andr. [Paeoniaceae; Cortex Moutan] (Mu-Dan-Pi). Network analysis highlighted primary treatment strategies with central components like Liu-Wei-Di-Huang-Wan, Paeonia suffruticosa Andr. [Paeoniaceae; Cortex Moutan] (Mu-Dan-Pi), Anemarrhena asphodeloides Bunge [Asparagaceae; Rhizoma Anemarrhenae] (Zhi-Mu), Rehmannia glutinosa (Gaertn.) DC. [Orobanchaceae; Radix Rehmanniae] (Sheng-Di-Huang), and Zhi-Bai-Di-Huang-Wan. Conclusion: This work underscores the pronounced renal and survival benefits associated with the seventeen PRCHMSLE in the treatment of SLE-CKD, concurrently mitigating the risks of hospitalization and hyperkalemia. This highlights their potential as alternative treatment options for individuals with this condition.

Association between Anti-Hepatitis C Viral Intervention Therapy and Risk of Sjögren's Syndrome: A National Retrospective Analysis.

Hepatitis C virus (HCV) infection is a potential risk factor for Sjögren's syndrome (SS). However, it is unclear whether anti-HCV intervention therapy could decrease SS risk. A retrospective cohort analysis from 1997-2012 comprising 17,166 eligible HCV-infected adults was conducted. By 1:2 propensity score matching, a total of 2123 treated patients and 4246 untreated patients were subjected to analysis. The incidence rates and risks of SS and death were evaluated through to the end of 2012. In a total follow-up of 36,906 person-years, 177 (2.8%) patients developed SS, and 522 (8.2%) died during the study period. The incidence rates of SS for the treated and untreated cohorts were 5.3 vs. 4.7/1000 person-years, and those of death for the treated and untreated cohorts were 10.0 vs. 14.8/1000 person-years. A lower risk of death (adjusted hazard ratio, 0.68; 95% CI, 0.53-0.87) was present in HCV-infected patients receiving anti-HCV therapy in multivariable Cox regression, and this remained consistent in multivariable stratified analysis. However, there were no relationships between anti-HCV therapy and its therapeutic duration, and SS risk in multivariable Cox regression. In conclusion, anti-HCV intervention therapy was not associated with lower SS risk in HCV-infected patients, but associated with lower death risk.

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.

Association between nucleos(t)ide analogue therapy for hepatitis B and Sjögren's syndrome: 15-year analysis of the national database of Taiwan.

Hepatitis B virus (HBV) infection has been proposed to play a role in the development of Sjögren's syndrome. However, to date, there are no reports on the risk of SS in HBV-infected patients following nucleos(t)ide analogue therapy. Due to Taiwan has higher prevalence of HBV infection and therapy was well recorded in the Taiwan's single-payer national health insurance database, we hypothesized that a long-term retrospective analysis of the risk of Sjögren's syndrome in HBV-infected patients following nucleotide therapy will increase our understanding of Sjögren's syndrome development following HBV infection. We identified 26,147 adults diagnosed with HBV infection between 1997 and 2012 in claims data. Finally, a total of 3268 HBV-infected patients who ever received nucleotide therapy (treated cohort) were frequency-matched on age and sex at 1:4 ratios to select a control group of 13,072 counterparts without therapy (untreated cohort). To identify Sjögren's syndrome risk, competing risk analysis adjusted for all covariates was performed. The risk was significantly lower in the treated cohort (15-year cumulative incidence, 2.4%; 95% confidence interval [CI], 1.4%-3.7%) than in the untreated cohort (7.1%; 95% CI, 2.5%-15.2%) (p = .015), and the adjusted HR was 0.6 (95% CI, 0.41-0.88; p = .009). Multivariable stratified analysis further verified the consistent associations between nucleoside therapy and risk reduction of Sjögren's syndrome across all strata. Our finding suggests that HBV infection treated with nucleotides is associated with lower risk of Sjögren's syndrome, implying a potential role of HBV infection in the development of Sjögren's syndrome.

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.

Applying Data Mining Techniques for Predicting Prognosis in Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a systematic chronic inflammatory disease. The disease mechanism remains unclear and may have resulted from autoimmune problems caused by genetic predisposing and pathogen infection. In clinical practice, selection of the initial treatment is based on the degree of disease activity, and treatment plans will be added gradually according to increased severity of the disease. However, treatment results can be unclear and treatment process uncertain and ambiguous, which can cause healthcare quality to become worse. This study attempts to combine expert opinions to construct various classifiers using a number of data mining techniques to analyze the different prognosis of two patient groups, by predicting whether the inflammatory indicator erythrocyte sedimentation rates of these two groups will be within the normal range with different medication strategies. Clinical data were collected for construction of different classifiers and we evaluate the prediction accuracy rate of each classifier afterwards. The optimum prediction model is selected from these classifiers to predict the prognosis of RA within these treatment strategies and analyze various results. The results show the accuracy rate of the prediction model by Logistic, SVM and DT module were 0.7927, 07829 and 0.9094, respectively. In the RA complications dataset, the accuracy rate of were 0.9393, 0.9290 and 0.9812, respectively. Futhermore, gain ratio was used to further analyze the rules and to discover which branch nodes are the most importance factor. The results of this study are helpful for formulation and development of guidelines for clinical RA treatments, and implementation of a decision support system by using the prediction model can assist medical staff to make correct decisions in the disease's early stage.

Moderate Risk of Hepatitis B Virus Reactivation in HBsAg-/HBcAb+ Carriers Receiving Rituximab for Rheumatoid Arthritis.

To investigate the incidence and risk factors of hepatitis B virus (HBV) reactivation in HBV surface antigen (HBsAg)-/ HBV core antibody (HBcAb)+ patients who underwent rituximab (RTX) therapy for rheumatoid arthritis (RA). From January 2000 through December 2017, a total of 134 RA patients with various HBV serostatuses who received RTX at Dalin Tzu Chi Hospital were screened. Finally, 50 HBsAg-/HBcAb+ patients were enrolled in this retrospective study. Baseline characteristics, comedications, and the occurrence of HBV reactivation were recorded. Four HBsAg-/HBcAb+ RA patients (8%; 4/50) experienced HBV reactivation after treatment with RTX. Hepatitis flare-up occurred in 2 of these 4 patients, with a fatal outcome in one. HBV reactivation occurred approximately 1-4 years after the first dose of RTX and 0.5-1.5 years after the last one. In HBsAg-/HBcAb+ patients, HBV reactivation was significantly more common in those who were HBV surface antibody (HBsAb)- at baseline than in those who were HBsAb+ (30% vs 4%; p = 0.02). A history of adalimumab use was associated with HBV reactivation (100% vs 39%; p = 0.02). A moderate risk of HBV reactivation was observed in HBsAg-/HBcAb+ RA patients receiving RTX therapy. The reactivation may induce acute hepatitis and even death. To reduce the risk of HBV reactivation, regular monitoring of liver function is insufficient; monitoring of viral load and HBsAg or prophylaxis with antiviral therapy should be considered.

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.

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.

Risk of rheumatoid arthritis in patients with hepatitis C virus infection receiving interferon-based therapy: a retrospective cohort study using the Taiwanese national claims database.

OBJECTIVES: To illuminate the association between interferon-based therapy (IBT) and the risk of rheumatoid arthritis (RA) in patients infected with hepatitis C virus (HCV). DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: This retrospective cohort study used Taiwan's Longitudinal Health Insurance Database 2005 that included 18 971 patients with HCV infection between 1 January 1997 and 31 December 2012. We identified 1966 patients with HCV infection who received IBT (treated cohort) and used 1:4 propensity score-matching to select 7864 counterpart controls who did not receive IBT (untreated cohort). OUTCOME MEASURES: All study participants were followed until the end of 2012 to calculate the incidence rate and risk of incident RA. RESULTS: During the study period, 305 RA events (3.1%) occurred. The incidence rate of RA was significantly lower in the treated cohort than the untreated cohort (4.0 compared with 5.5 per 1000 person-years, p<0.018), and the adjusted HR remained significant at 0.63 (95% CI 0.43 to 0.94, p=0.023) in a Cox proportional hazards regression model. Multivariate stratified analyses revealed that the attenuation in RA risk was greater in men (0.35; 0.15 to 0.81, p=0.014) and men<60 years (0.29; 0.09 to 0.93, p=0.036). CONCLUSIONS: This study demonstrates that IBT may reduce the risk of RA and contributes to growing evidence that HCV infection may lead to development of RA.

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.