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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., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2021 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

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 × 10 7  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., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

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.

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.

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

Contexts: CD154 (commonly referred to as CD40-ligand) is a critical T cell factor that participates in the pathogenesis of autoimmune and is over-expressed in rheumatoid arthritis (RA). TNF-α blockade treatment had dramatic efficacy in RA., Objective: To investigate whether TNF-α blockade treatment can inhibit CD154 expression in RA., Methods: Blood samples were collected from 33 patients with rheumatoid arthritis before and 3 months after TNF-α blockade treatment. Clinical serological data determined by standard assays and T cell CD154 expression levels determined by flow cytometry were statistically analyzed for these two time points., Results: The percentage of CD154 expression on gated CD4+ T cells of PBMCs from RA patients after 3 months TNF-α blockade treatment was significantly lower than before treatment (2.94 ± 3.21% vs. 7.21 ± 5.64%; p = 0.0001). The disease activity and anti-CCP antibody levels were also significantly reduced after TNF-α blockade treatment. The CD154 expression levels were positively correlated with disease activity index DAS28, and CRP. The post-stimulated CD154 expression percentage of purified CD4+ T cells between baseline and after TNF-α blockade treatment was not significantly different (p = 0.221). Baseline CD154 levels were positively correlated with treatment-induced changes in DAS28 (p = 0.014; r2 = 0.187)., Conclusions: TNF-α blockade treatment significantly decreased the CD154 expression on CD4+ T cells, disease activity and anti-CCP antibody simultaneously in RA patients. However TNF-α blockade did not impair T cell capacity to express CD154 after stimulation. These results suggest that decreased CD154 expression after TNF-α blockade may be due to decreased RA disease activity but not direct inhibition of CD154 responsiveness of T cells.

The aim of this study was to evaluate whether the presence of aberrantly expressed lncRNAs could promote T cell inflammatory responses in patients with RA. The expression levels of 10 potential aberrantly expressed lncRNAs were evaluated in T cells from 39 patients with RA and 17 controls using real-time reverse transcription polymerase chain reaction. The aberrantly expressed lncRNAs were measured in Jurkat cells co-cultured with or without ionomycin and phorbol 12-myristate 13-acetate. Transfection studies using small interfering RNA (siRNA) were conducted for biological functions, and microarray analysis was performed to search for target genes of specific lncRNAs. We confirmed that the expression levels of LOC100652951 and LOC100506036 were higher in RA T cells compared with controls. RA patients treated with biologic agents had lower expression levels of LOC100652951, and female RA patients had lower LOC100506036 expression levels after multivariate analysis. After activation, the expression levels of LOC100506036, but not LOC100652951, increased in Jurkat cells. Transfection of siRNA targeting LOC100506036 inhibited interferon gamma production and the expression of nuclear factor of activated T cells in activated Jurkat cells. After the microarray analysis with validation, inhibition of LOC100506036 expression by siRNA leaded to the decreased expression of sphingomyelin phosphodiesterase 1 (SMPD1). In conclusion, the expression levels of LOC100652951 and LOC100506036 were increased in RA T cells. Treatment with biologic agents could lower the expression of LOC100652951 in RA T cells. LOC100506036 could regulate the expression of SMPD1 and NFAT1 and could contribute to the inflammatory responses in RA.

Abnormal Ca(2+) -mediated signalling contributes to the pathogenesis of rheumatoid arthritis (RA). However, the potential implication of calcium channel blocker in RA remained unknown. We hypothesized that nifedipine, an L-type calcium channel blocker, combined with a calcineurin inhibitor, could suppress T cell activation via targeting different level of the Ca(2+) signalling pathway. The percentage of activated T cells and the apoptotic rate of mononuclear cells (MNCs) was measured by flow cytometry. The MNC viability, cytokine production, cytosolic Ca(2+) level and activity of the nuclear factor of activated T cells (NFAT) were measured by enzyme-linked immunosorbent assay (ELISA). The NFAT-regulated gene expression, including interleukin (IL)-2, interferon (IFN)-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF), was measured by real-time polymerase chain reaction (PCR). We found that the percentage of activated T cells in anti-CD3 + anti-CD28-activated MNC was higher in RA patients. High doses of nifedipine (50 µM) increased MNCs apoptosis, inhibited T cell activation and decreased T helper type 2 (Th1) (IFN-γ)/Th2 (IL-10) cytokine production in both groups. The Ca(2+) influx was lower in anti-CD3 + anti-CD28-activated MNC from RA patients than healthy volunteers and suppressed by nifedipine. When combined with a subtherapeutic dose (50 ng/ml) of cyclosporin, 1 µM nifedipine suppressed the percentage of activated T cells in both groups. Moreover, this combination suppressed more IFN-γ secretion and NFAT-regulated gene (GM-CSF and IFN-γ) expression in RA-MNCs than normal MNCs via decreasing the activity of NFATc1. In conclusion, we found that L-type Ca(2+) channel blockers and subtherapeutic doses of cyclosporin act additively to suppress the Ca(2+) -calcineurin-NFAT signalling pathway, leading to inhibition of T cell activity. We propose that this combination may become a potential treatment of RA., (© 2012 The Authors. Clinical and Experimental Immunology © 2012 British Society for Immunology.)

Objective: Sensitive noninvasive strategies for monitoring treatment response in rheumatoid arthritis (RA) would be valuable for facilitating appropriate therapy and dosing, evaluating clinical outcome, and developing more effective drugs. Because different proteases are highly up-regulated in RA and contribute significantly to joint destruction, in the present study we investigated whether such enzymes are suitable in vivo imaging biomarkers for early evaluation of treatment response in a murine model of RA., Methods: Using a protease-activated near-infrared fluorescence (NIRF) imaging "smart" probe, we examined the presence and distribution of fluorescence in arthritic joints of mice with collagen-induced arthritis by both noninvasive fluorescence imaging and histology. Proteases that target the Lys-Lys cleavage site, including cathepsin B, activate probe fluorescence. Treatment monitoring data were obtained following methotrexate (MTX) therapy., Results: Twenty-four hours after intravenous injection of the protease sensor, affected toes and paws of arthritic mice showed significantly higher fluorescence intensity than did toes and paws of healthy mice. Fluorescence from the protease probe and cathepsin B antibody histologic staining were localized in the vast majority of cells in the inflamed synovium. In arthritic animals treated with MTX (35 mg of MTX/kg 48 hours prior to probe injection), a significantly lower fluorescent signal (inflamed paws 50%, inflamed toes 70%) was observed as compared with untreated arthritic animals., Conclusion: Protease-activated NIRF probes are sensitive means of imaging the presence of target enzymes in arthritic joints and can be used for early monitoring of treatment response to antirheumatic drugs such as MTX.