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Objective: To evaluate the long-term safety and effectiveness of tocilizumab (TCZ) for the treatment of rheumatoid arthritis (RA) in a real-world clinical setting in Taiwan., Method: All refractory RA patients who initiated intravenous TCZ between August 2012 and March 2015 were enrolled. Data on patient characteristics, drug safety and effectiveness were collected., Results: A total of 114 RA patients were recruited. Despite the majority of them (93%) had previous biologic failure, 43.75% of the patients were able to reach ACR50 after one year. Serious adverse events commonly found were bacterial pneumonia (4.24/100 patient-years) followed by cellulitis (2.12/100 patient-years). Twenty-three patients had old or latent TB infections, 11 patients had chronic hepatitis B. During the 3 years follow-up, none of them had reactivation of TB, or hepatitis B with concomitant use of isoniazid prophylaxis or pre-emptive antiviral treatment., Conclusion: In this 3-year real-world study on RA patients of Taiwan, we found a good long-term effectiveness and similar safety profiles for the TCZ treatment. With prophylactic strategy for latent TB and pre-emptive antiviral treatment for HBV carriers, the risk of reactivation of latent TB and HBV may be reassured., (Copyright © 2017. Published by Elsevier B.V.)

Rheumatoid arthritis (RA) is associated with a high risk of osteoporosis and fracture. Interleukin (IL)-6 inhibitors may suppress osteoclast activation. Anticitrullinated protein antibody (ACPA) titers are inversely associated with bone mineral density (BMD). However, the differential effect of ACPA on bone turnover marker (BTM) and BMD changes after IL-6 inhibition remains unclear. This prospective study recruited patients with active RA with inadequate response to methotrexate or biologics. BMD was measured before and after 2-year tocilizumab (TCZ) treatment. Serum osteocalcin, N-terminal propeptide of type I collagen (P1NP), and C-terminal cross-linking telopeptide of type I collagen (CTX) levels were assessed at the baseline and after treatment. We enrolled 76 patients with RA (89.5% women, age: 57.2 ± 13.3 years) receiving TCZ. The 28-joint disease activity score was negatively correlated with BMD and T-scores of the lumbar spine and bilateral femoral neck. ACPA-positive patients had lower lumbar spine and femoral neck T-scores. After 2-year TCZ treatment, CTX levels significantly decreased (0.32 ± 0.21 vs. 0.26 ± 0.17, p = 0.038). Femoral neck BMD increased significantly (0.71 ± 0.22 vs. 0.69 ± 0.55, p = 0.008). Decreased CTX levels and improved BMD were observed only in ACPA-positive patients. After treatment, femoral neck BMD significantly increased only in patients receiving a glucocorticoid dose of ≥5 mg/day. Two-year TCZ treatment reduced bone resorption and increased femoral BMD in ACPA-positive patients. The net effects of glucocorticoids and IL-6 inhibition on BMD imply that strict inflammation control might affect bone metabolism.

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

Introduction: The goal of this study was to investigate (1) the associations of rheumatoid arthritis (RA)-related inflammation or rheumatoid factor/anti-cyclic citrullinated peptide (anti-CCP) positivity with lipid profiles and insulin resistance (IR), (2) the effects of biologic therapy on lipid profiles and IR, and (3) potential predictors for the presence of subclinical atherosclerosis., Methods: Serum levels of lipid profiles were determined by enzymatic methods in 32 adalimumab-treated patients, 16 etanercept-treated patients, 24 tocilizumab-treated patients, and 20 biologic-naïve patients. Atherogenic index, which corresponds to the ratio of total cholesterol to high-density lipoprotein cholesterol (HDL-C), was calculated. IR was measured by homeostasis model assessment. Pro-inflammatory cytokine levels were examined by enzyme-linked immunosorbent assay. Common carotid artery intima-media thickness was determined by using sonography., Results: There was an inverse correlation between disease activity (disease activity score for 28 joints, or DAS28) and low-density lipoprotein cholesterol (LDL-C) levels (r=-0.226, P<0.05) and a positive correlation between DAS28 and IR (r=0.361, P<0.005). Anti-CCP-positive patients had significantly higher DAS28 and IR compared with anti-CCP-negative patients. There was also a positive correlation between IR and levels of interleukin-6 or tumor necrosis factor-alpha (TNF-α). HDL-C levels significantly increased in patients receiving 6-month anti-TNF-α therapy, and levels of total cholesterol, LDL-C, and triglyceride increased in tocilizumab-treated patients. IR significantly decreased in patients under biologic therapy but was unchanged in biologic-naïve patients. Age, IR, and DAS28 were significant predictors of severe subclinical atherosclerosis (odds ratios of 1.08, 2.77, and 2.52, respectively)., Conclusions: Significant associations of RA-related inflammation with lipid profiles and IR indicate the involvement of RA in atherosclerosis pathogenesis. Biologic therapies were associated with IR reduction without change in atherogenic index, but their beneficial effects on atherosclerosis reduction need to be verified in the future.

Objective: To evaluate the associations between (1) antidrug antibody (ADAb) and therapeutic response, (2) ADAb and serum drug trough levels and (3) serum drug levels and therapeutic responses in rheumatoid arthritis (RA) patients receiving adalimumab or etanercept. Secondarily, we aim (1) to evaluate the concordance between radioimmunoassay and bridging ELISA for ADAb assessment and to evaluate the correlation between two different ELISA methods for detecting drug levels, and (2) to determine the optimal cut-off drug levels for good European League Against Rheumatism (EULAR) response., Methods: ADAb levels were determined by bridging ELISA and radioimmunoassay, and drug levels evaluated using sandwich ELISA among 36 adalimumab-treated patients and 34 etanercept-treated patients at the 6th and 12th month. The optimal cut-off drug levels for EULAR responses were determined by receiver-operating characteristic curve analysis., Results: ADAb was detected in 10 (27.8%) and 13 (36.1%) of adalimumab-treated patients after 12-month therapy using bridging ELISA and radioimmunoassay respectively, but not detected in any of etanercept-treated patients. The presence of ADAb was associated with lower EULAR response and lower drug levels compared with those without ADAb (both p<0.001). Drug trough levels were positively associated with DAS28 decrement (ΔDAS28) (all p<0.001). The optimal cut-off trough levels for adalimumab were 1.274 μg/mL and 1.046 μg/mL, and those for etanercept were 1.242 μg/mL and 0.800 μg/mL for good EULAR response assessed at the 6th and 12th month, respectively., Conclusions: ADAb levels were inversely correlated with therapeutic response and drug levels. The positive correlation between drug levels and ΔDAS28 indicates that drug monitoring would be useful to evaluate therapeutic response of TNF-α inhibitors., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objectives: The risk of active tuberculosis increases in rheumatoid arthritis (RA) patients receiving antitumour necrosis factor alpha (TNFα) therapy. Longitudinal data concerning serial interferon γ (IFNγ) assays for detecting tuberculosis have been limited. This study investigated the time course of the development of active tuberculosis, and evaluated the utility of serial QuantiFERON-TB Gold (QFT-G) assays for detecting its emergence in RA patients undergoing long-term anti-TNFα therapy., Methods: 242 RA patients who received anti-TNFα therapy and serial QFT-G assays were prospectively evaluated. QFT-G was performed by measuring IFNγ levels in whole blood treated with tuberculosis-specific antigens., Results: Among 242 RA patients, 75 (31.0%) had a positive tuberculin skin test (TST) and 45 (18.6%) had positive QFT-G results, with another nine (3.7%) showing indeterminate QFT-G assay. Isoniazid prophylaxis was given to 37 patients with TST+/QFT-G+ results and 24 TST+/QFT-G- patients with TST induration diameter ≧10 mm. Four patients (three with baseline QFT-G+ results) developed tuberculosis within the first 3 months of anti-TNFα therapy, whereas five patients with baseline TST-/QFT-G- results developed active tuberculosis after 20-24 months' anti-TNFα therapy. Progressively rising levels of released IFNγ (2.17 ± 0.98 vs 5.93 ± 2.92 IU/ml in early secretory antigenic target-6-stimulated well; 1.12 ± 0.84 vs 2.96 ± 1.02 IU/ml in culture filtrate protein-10-stimulated well) were observed in those who developed tuberculosis early in anti-TNFα therapy. QFT-G conversion was found in baseline QFT-G-negative patients who developed tuberculosis late in treatment., Conclusion: The emergence of active tuberculosis follows a biphasic pattern. Persistently high levels of released IFNγ or QFT-G conversion strongly indicate the development of active tuberculosis in patients undergoing long-term anti-TNFα therapy.

Objective: To investigate the kinetics of hepatitis B virus (HBV) viral loads and HBV reactivation in rheumatoid arthritis (RA) patients undergoing therapy with tumour necrosis factor alpha (TNFα) inhibitors., Methods: The authors investigated the virological, serological and biochemical evidence of HBV reactivation in 88 RA patients receiving anti-TNFα therapy. Levels of HBV surface (HBs) antigen (Ag), anti-HBV core (HBc)-IgG and anti-HBs antibody (Ab) were detected by electrochemiluminescence immunoassay, and viral loads were determined by real-time PCR assay., Results: In a total of 88 HBcAb-positive patients, 18 (20.5%) patients were HBsAg-positive, 12 (13.6%) patients were HBsAg-negative/HBsAb-negative and 58 (65.9%) patients were HBsAg-negative/HBsAb-positive before starting anti-TNFα therapy. Among HBsAg-positive patients receiving anti-TNFα therapy, HBV reactivation was documented in none of 10 patients who received lamivudine pre-emptive therapy and serum viral loads significantly decreased (mean ± SEM, 153,860 ± 80,120 IU/ml at baseline vs 313 ± 235 IU/ml after 12 months antiviral therapy, p<0.001), paralleling the decrease in serum aminotransferase levels. In contrast, five (62.5%) of eight patients without antiviral prophylaxis developed HBV reactivation, viral loads significantly increased after anti-TNFα therapy (9375 ± 5924 IU/ml vs 49,710,000 ± 40,535,000 IU/ml, p<0.001), and markedly declined after antiviral therapy (49,710,000 ± 40,535,000 IU/ml vs 6382 ± 2424 IU/ml, p<0.001). Baseline viral loads were detectable in four (33.3%) of 12 patients who had HBsAg-negative/HBsAb-negative status, and one developed HBV reactivation after anti-TNFα therapy., Conclusion: HBV reactivation can occur in both HBsAg-positive and HBsAg-negative/HBcAb-positive patients with detectable HBV DNA, so-called occult HBV infection, during anti-TNFα therapy. Antiviral prophylaxis may effectively reduce HBV reactivation in HBsAg-positive RA patients undergoing anti-TNFα therapy.

Introduction: The objective of this study was to investigate the effects of tumor necrosis factor (TNF)-α inhibitors on circulating T helper-type 17 (Th17) cells and Th17-related cytokines in patients with rheumatoid arthritis (RA)., Methods: The frequencies of circulating Th17 cells and serum levels of Th17-related cytokines were determined using flow cytometry analysis and ELISA, respectively, in 48 RA patients both before (baseline) and six months after anti-TNF-α therapy. Therapeutic response was evaluated using European League Against Rheumatism (EULAR) response criteria., Results: Significantly higher baseline frequencies of circulating Th17 cells and serum levels of interleukin (IL)-6, IL-17, IL-21, IL-23 and TNF-α were observed in active RA patients than in 12 healthy controls (all P < 0.001). After anti-TNF-α therapy, 36 patients (75%) were EULAR responders (20 good responders and 16 moderate responders) and 12 (25.0%) were non-responders. The mean levels of circulating Th17 cells and IL-17 significantly decreased (1.13% vs. 0.79%; 43.1 pg/ml vs. 27.8 pg/ml; respectively, both P < 0.001) in parallel with clinical remission in responders. Levels of IL-6, IL-21, IL-23 and TNF-α were significantly decreased after anti-TNF-α therapy in responders. In contrast, the mean levels of circulating Th17 cells and IL-17 significantly increased after anti-TNF-α therapy (2.94% vs. 4.23%; 92.1 pg/ml vs. 148.6 pg/ml; respectively, both P < 0.05) in non-responders. Logistic regression analysis identified a high baseline level of IL-17 as a significant predictor of poor therapeutic response., Conclusions: The beneficial effect of anti-TNF-α therapy might involve a decrease in Th17-related cytokines in responders, whereas rising levels of circulating Th17-cells and IL-17 were observed in patients with an inadequate response to anti-TNF-α therapy.

Background/purpose: Adalimumab is a fully humanized monoclonal antibody that blocks tumor necrosis factor (TNF)-alpha, which is effective in the treatment of patients with rheumatoid arthritis (RA). The purpose of this study was to compare the efficacy and safety of adalimumab plus methotrexate (MTX) and MTX alone in Taiwanese patients with active RA., Methods: Forty-seven patients with active RA who were maintained on MTX therapy at a stable dose of 10-15 mg/week for 4 weeks were randomized blindly to receive adalimumab 40 mg (n = 35) or placebo (n = 12) by subcutaneous injection every other week over a period of 12 weeks. The primary endpoint was a reduction in tender and swollen joint counts of 20% (ACR20), 50% (ACR50) and 70% (ACR70), as determined by the American College of Rheumatology criteria in week 12. The occurrence of treatment-emergent adverse events (TEAEs) was the primary safety variable., Results: Addition of adalimumab to MTX resulted in a significant reduction in the number of swollen joints (12.6 vs. 5.6; p = 0.011), patients' global assessment of disease activity (18.0 vs. 4.8; p = 0.040), pain visual analog scale (18.3 vs. 1.3; p = 0.015), and disability indices of the Health Assessment Questionnaire (0.6 vs. 0.2; p = 0.031), compared with MTX alone after 12 weeks of therapy. Overall improvement in disease activity was assessed by ACR20 (54.3% vs. 33.3%), ACR50 (34.3% vs. 16.7%) and ACR70 (14.3% vs. 0%), and all favored the adalimumab plus MTX group. TEAEs were comparable between the treatment groups, except for a slightly higher incidence of severe infection in the adalimumab plus MTX group., Conclusion: Adalimumab in combination with MTX is well tolerated and provides significantly more clinical benefits than MTX alone in Taiwanese patients with active RA.

Objective: To investigate QuantiFERON-tuberculosis Gold (QFT-G) assay and tuberculin skin test (TST) for latent tuberculosis (TB) infection (LTBI) in patients with rheumatoid arthritis (RA) treated with adalimumab., Methods: We prospectively followed up 43 RA patients who received adalimumab therapy and underwent serial TSTs and QFT-G assays. TST was performed using Mantoux method and QFT-G assay was examined by measuring interferon-gamma levels in whole blood samples that were incubated with early secretary antigenic target-6 and culture filtrate protein 10., Results: Before starting adalimumab therapy, 8 RA patients (18.6%) had positive and 35 (81.4%) had negative TST results. All 8 RA patients with positive TST results were diagnosed as LTBI and received isoniazid prophylaxis (INHP) 1 month before starting adalimumab therapy. None of these 8 RA patients developed active TB 2 years after completing INHP. A high rate (10 [37.0%] patients) of TST conversion was observed among 27 patients who had completed 12-month adalimumab therapy. Of these 10 patients with TST conversion, 2 patients had positive QFT-G results and 1 developed active TB disease. Among 17 RA patients who did not have TST conversion after 12-month adalimumab therapy, 1 patient who had a positive QFT-G result developed active TB disease. Of all 43 RA patients who received adalimumab therapy, 4 (9.3%) developed active TB after starting adalimumab therapy., Conclusion: The application of TST for detecting LTBI is limited in RA patients by the frequent presence of anergy. Combined QFT-G assay and TST can aid in detecting LTBI in RA patients receiving adalimumab therapy.