Major depression and clinical outcomes in patients with heart failure with preserved ejection fraction.

OBJECTIVE: Limited data have been published concerning about depression in heart failure with preserved ejection fraction (HFpEF). Besides, among HFpEF patients with depression, the efficacy of antidepressants is poorly defined. Therefore, our current study was aimed to examine the relationship between major depression and clinical outcomes in HFpEF patients and further address the effects of antidepressants on prognosis in patients with major depression and HFpEF. METHODS: A total of 1431 patients enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT) were divided into 2 groups according to the baseline depression status. Major depression was diagnosed if the Patient Health Questionnaire-9 score (PHQ-9) ≥ 10. Univariable and multivariable Cox proportional hazards models tested the association of major depression with outcomes and the effects of antidepressants among HFpEF patients with major depression during a follow-up of 6 years. RESULTS: 26.7% (382/1431) of patients were diagnosed with major depression. After multivariable adjustment, major depression at baseline was not significantly associated with cardiovascular outcomes (fully adjusted hazard ratio (aHR) 0.95 [0.76-1.18] for primary outcomes; aHR: 0.86 [0.67-1.10] for HF hospitalization; aHR: 1.06 [0.91-1.23] for any hospitalization; aHR: 1.00 [0.70-1.43] for cardiovascular death; aHR: 1.24 [0.96-1.61] for all-cause death). Additionally, among HFpEF patients with major depression, the use of antidepressants was not associated with adverse events (P > .05 for all analyses). CONCLUSIONS: In HFpEF patients, major depression at baseline did not increase mortality or rehospitalization. Additionally, treatment with antidepressants might not improve prognosis among HFpEF patients with major depression. Future studies are warranted to explore the effects of antidepressants on HFpEF patients with depression.

Comparison of efficacy and safety of urate-lowering therapies for hyperuricemic patients with gout: a meta-analysis of randomized, controlled trials.

OBJECTIVES: To assess the efficacy and safety of the commonly used urate-lowering therapies (ULTs): febuxostat, allopurinol, and lesinurad in hyperuricemic patients with gout. METHODS: We included all randomized controlled trials (RCTs) that compared ULTs with placebo or head to head. The primary efficacy endpoint was the proportion of subjects achieving the target serum urate (SU) level at month 6. Safety outcomes included total adverse events (AEs), serious AEs, withdrawals due to AEs, and AEs per organ system. A Bayesian network model was used to compare all ULTs with placebo and among themselves. RESULTS: Fifteen RCTs were included for the analysis, in which 7968 patients were randomly assigned to take either placebo or one of 11 ULTs: allopurinol, febuxostat 40/80/120/240 mg/day, lesinurad 400 mg/day, lesinurad 200/400/600 mg/day plus allopurinol, and lesinurad 200/400 mg/day plus febuxostat. All ULTs were effective in achieving the target SU level at month 6 compared with placebo (ORs between 26.81 and 1928). Febuxostat 80/120/240 mg/day was superior to allopurinol and well tolerated for urate reduction. And as febuxostat dosage increased, more patients achieved the target SU level. Furthermore, the lesinurad combination with xanthine oxidase inhibitor (XOI) groups had a higher proportion of patients achieving the target SU level than the febuxostat 40 mg/day group (ORs between 2.89 and 9.17), the allopurinol group (ORs between 3.56 and 11.27), or the lesinurad 400 mg/day monotherapy group (ORs between 12.30 and 39.17) but might have a high risk of AEs. CONCLUSIONS: All ULTs are effective in achieving the target SU level compared with placebo in hyperuricemic patients with gout. Lesinurad in combination with febuxostat or allopurinol is effective in urate lowering, especially for patients with inadequate response to XOI monotherapy. Key Points • All urate-lowering therapies (ULTs) were effective in achieving the target serum urate (SU) level at month 6 compared with placebo in hyperuricemic patients with gout. • Febuxostat 80/120/240 mg/day was superior to allopurinol and well tolerated for urate reduction. And as febuxostat dosage increased, more patients achieved the target SU level. • Lesinurad in combination with febuxostat or allopurinol was effective in urate lowering, especially for patients with inadequate response to xanthine oxidase inhibitor monotherapy, but might have a high risk of AEs.

Hsa_circ_0088036 promotes the proliferation and migration of fibroblast-like synoviocytes by sponging miR-140-3p and upregulating SIRT 1 expression in rheumatoid arthritis.

Circular RNAs (circRNAs) have been demonstrated to play crucial roles in the development and progression of various types of cancers by serving as microRNA sponges to regulate the expression of target genes. Although in-depth studies of circRNAs have been conducted, their functional and pathological significance in autoimmune diseases, including rheumatoid arthritis (RA), remains unclear. Our previous study verified that hsa_circ_0088036 (circ0088036) is significantly elevated in peripheral blood mononuclear cells from patients with RA. The present study aimed to explore the roles of circ0088036 in the pathogenesis of RA. The circ0088036/miR-140-3p/silent information regulator 1 (SIRT 1) axis was predicted by bioinformatics tools. Circ0088036 was found to be aberrantly upregulated in fibroblast-like synoviocytes (FLSs) in RA compared with FLSs in osteoarthritis (OA). Functionally, upregulated circ0088036 promoted the proliferation and migration of RA-FLSs. Mechanistically, circ0088036 acted as a miR-140-3p sponge to upregulate SIRT 1 expression, subsequently promoting RA progression. In conclusion, this study revealed that circ0088036 may play an essential role in promoting synovial pathogenesis via the circ0088036/miR-140-3p/SIRT 1 axis in RA, providing new insight into circRNAs during RA progression.

Indirect comparison of NSAIDs for ankylosing spondylitis: Network meta-analysis of randomized, double-blinded, controlled trials.

Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by lower back pain, enthesitis and asymmetrical peripheral arthritis. Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended as a first-line drug treatment for AS. The aim of the present study was to evaluate the efficacy and safety of NSAIDs in patients with active AS. A total of 9 randomized controlled trials focusing on 6 NSAIDs, including etoricoxib, celecoxib, meloxicam, diclofenac, naproxen and beta-D-mannuronic acid (M2000), were analyzed in the present study. The efficacy endpoints included total pain score, patients' global assessment of disease activity (PGA), Bath Ankylosing Spondylitis Functional Index (BASFI) and the rate of achieving an Assessment in Ankylosing Spondylitis 20% response (ASAS20). The safety endpoints included total adverse events (AEs), gastrointestinal (GI) AEs, withdrawals due to AEs and serious AEs. NSAIDs were compared with the placebo and among themselves using Bayesian network meta-analysis, calculating mean differences (MDs) for continuous data and odds ratios for dichotomous data. The analysis revealed that all NSAIDs were significantly more effective in reducing pain severity than placebo (MDs between -17.49 and -25.99). Similarly, significant improvements in PGA, BASFI and ASAS20 were determined in patients receiving NSAIDs. Furthermore, etoricoxib was ranked as the most efficacious treatment for patients with AS. With regard to safety, there were no significant differences between NSAIDs and placebo in terms of total AEs, withdrawals due to AEs or serious AEs. Furthermore, no significant differences in AEs were identified between M2000 and the placebo. However, patients treated with diclofenac and naproxen had a higher risk of GI events than those taking placebo. In conclusion, the NSAIDs were all highly effective and well-tolerated in the treatment of AS. However, clinicians should take GI toxicity into account when prescribing NSAIDs.

Erratum: Efficacy and safety of loxoprofen hydrogel patch versus loxoprofen tablet in patients with ankylosing spondylitis: A 4-week randomized, open-label study.

[This corrects the article DOI: 10.3892/br.2019.1209.].

Transforming growth factor ß1 promotes fibroblast-like synoviocytes migration and invasion via TGF-ß1/Smad signaling in rheumatoid arthritis.

Migration and invasion are important characteristics of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs), which are involved in joint damage and contribute to rheumatoid arthritis (RA) pathology. However, the underlying mechanisms remain unclear. Because epithelial-mesenchymal transition (EMT) is a key mechanism related to migration and invasion in cancer cells, we investigated the relationship between EMT and RA-FLSs and explored whether the transforming growth factor ß1 (TGF-ß1)/Smad signaling pathway is involved. In vivo, fibroblast-like synoviocytes (FLSs) were isolated from the synovium of RA or osteoarthritis (OA) patients and cultured for 4-8 passages. EMT markers were detected by immunofluorescence and Western blotting. RA-FLSs were treated with TGF-ß1 or Smad2/3 small interfering RNA (siRNA), EMT markers were detected, and migration and invasion were assessed by Transwell assays. EMT markers could be detected in FLSs; when compared with osteoarthritis fibroblast-like synoviocytes (OA-FLSs), E-cadherin and vimentin decreased, while N-cadherin and α-smooth muscle actin (α-SMA) increased in RA-FLSs. Furthermore, TGF-ß1 enhanced migration and invasion by inducing EMT via activating Smad2/3 in RA-FLSs. Phosphorylation of Smad2/3 was accompanied by degradation of Smad3. Silencing Smad2/3 blocked EMT and inhibited the migration and invasion induced by TGF-ß1. Matrix metalloproteinase 9 (MMP9) and vimentin were not affected when cells were treated with TGF-ß1 or Smad2/3 siRNA. The TGF-ß1/Smad signaling pathway is involved in EMT and contributes to migration and invasion in RA-FLSs. Interestingly, vimentin decreased in RA-FLSs, but there is no correlation between vimentin and TGF-ß1/Smad signaling pathway. Thus, further research on vimentin should be conducted.

Efficacy and safety of loxoprofen hydrogel patch versus loxoprofen tablet in patients with ankylosing spondylitis: A 4-week randomized, open-label study.

The aim of the present study was to assess the efficacy and safety of loxoprofen sodium hydrogel patch (LX-P) vs. loxoprofen sodium tablet (LX-T) in patients with active ankylosing spondylitis (AS). The study population consisted of patients who met the modified New York radiographic criteria for AS and had active disease. Patients were randomly assigned to either the LX-P group (LX-P 100 mg per day) or LX-T group (LX-T 60 mg 3 times daily) for 4 weeks. The primary efficacy endpoint was the percentage of patients reaching Assessment in Ankylosing Spondylitis 20% (ASAS20) response at week 4. Secondary efficacy outcomes included ASAS5/6 response rate and changes from baseline to week 4 for Ankylosing Spondylitis Disease Activity Score, patient's global assessment of disease activity, and pain score. Of the 70 randomized patients included, 35 patients were allocated to the LX-P group and 35 to the LX-T group. No significant differences were observed between the LX-P and LX-T groups in the proportion of patients achieving ASAS20 response at week 4 (54.3 vs. 74.3%; P=0.081), nor in the ASAS5/6 response and changes of efficacy outcomes between the two groups. Furthermore, patients without peripheral arthritis in the LX-P group were more likely to achieve ASAS20 response. There was a decreased incidence of gastrointestinal adverse events in the LX-P group, but this was not significant. There was no significant differences in efficacy and safety between topical LX-P and oral LX-T administration for patients with active AS.

Long-term prognosis and quality of life in patients with early rheumatoid arthritis treated according to the 2015 ACR guideline (LELAND): protocol for a multicentre prospective observational study in Southern China.

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic systemic disease and one of the most disabling diseases for patients. The American College of Rheumatology (ACR) issued a new guideline in 2015 for the treatment of RA based on the treat-to-target strategy to achieve better outcomes. This study will focus on the real-world rates of remission and low disease activity of patients with early RA in China, who will be treated according to the 2015 ACR guideline. Additionally, factors influencing treat-to-target outcomes will be analysed, and long-term prognosis and quality of life will be assessed. METHOD AND ANALYSIS: Two-hundred patients with early RA will be enrolled, treated and followed up once every 3 months for 48 months. These patients should fulfil the 2010 RA classification criteria of the ACR/European League Against Rheumatism with a disease course of no more than 6 months and should also fulfil other eligibility criteria. The patients will be treated following the 2015 ACR guideline. Their disease activity will be assessed, and they will be instructed to complete several questionnaires once every 3 months. The primary outcomes are the Disease Activity Score on 28 joints and Health Assessment Questionnaire Disability Index. The secondary outcome variables are the Simplified Disease Activity Index, Clinical Disease Activity Index and Routine Assessment of Patient Index Data 3 results, imaging data and personal medical costs. The data will be analysed using appropriate statistical analyses. ETHICS AND DISSEMINATION: This research was approved by the Nanfang Hospital Ethics Committee (NFEC-2017-192). The results of the study will be published in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03508713; Pre-results.

Effects and safety of 99Tc-MDP in patients with refractory ankylosing spondylitis: a 2-stage (30-week follow-up) clinical trial.

OBJECTIVES: To evaluate the clinical efficacy and safety in patients with refractory ankylosing spondylitis (AS) initiating 99Tc-MDP therapy and explore the mechanisms. METHODS: Refractory AS patients were enrolled in the clinical trial and received 99Tc-MDP treatments for 3 or 5 courses according to ASAS improvement. Efficacy and safety evaluations were conducted during the follow-up. 37 cytokines were quantified by Luminex at baseline and week 30. p-values<0.05 were considered statistically significant. RESULTS: 51 refractory AS patients were included, with 20 healthy people serving as the control group. The patients were in an active disease state (mean (SD) ASDAS 3.66 (0.83), BASDAI 4.53 (1.92)), 42(82.35%) patients had syndesmophytes. Their cytokines were significantly higher than that in the control group. After 3 courses of 99Tc-MDP treatment, 32 (62.75%) patients achieved ASAS20 improvement, 24 (47.06%) patients achieved a clinically significant improvement (ΔASDAS-CRP≥1.1). 27 patients entered the second stage to complete 5 courses of the treatment, all of whom achieved ASAS20 improvement, 18 (66.67%) patients achieved a clinically significant improvement. All clinical parameters including ASAS and ASDAS significantly improved as the treatment was continued. Cytokines also had significant down-regulation after the treatment, and the reductions had positive correlations with the improvements of disease activity. No serious adverse event was observed. CONCLUSIONS: This investigation confirmed the remarkable efficacy of 99Tc-MDP in a large number of refractory AS patients, and highlighted the mechanism by dramatic regulation on cytokines. 99Tc-MDP was safe in clinical application.

Efficacy and safety of antithrombotic regimens after coronary intervention in patients on oral anticoagulation: Traditional and Bayesian meta-analysis of clinical trials.

OBJECTIVE: To perform a systematic review and meta-analysis to assess the efficacy and safety of diverse antithrombotic regimens in patients on long-term anticoagulation after percutaneous coronary intervention (PCI). METHODS: After searching electronic database (up to 27 June 2015), we included trials comparing dual antiplatelet therapy (aspirin plus clopidogrel), oral anticoagulant (OAC) plus clopidogrel, OAC plus aspirin, or triple therapy (OAC with clopidogrel and aspirin). Efficacy outcomes were major adverse cardiovascular event (MACE), ischemic stroke, myocardial infarction (MI), and all-cause mortality; safety outcomes included major bleeding and any bleeding. We conducted both traditional and Bayesian network meta-analysis, computing pooled odds ratio (OR) with 95% confidence intervals (CI) to compare diverse antithrombotic therapies simultaneously. RESULTS: Eighteen trials were included in the quantitative analysis. OAC plus clopidogrel and triple therapy were associated with a lower risk of MACE, ischemic stroke, MI and all-cause mortality compared with dual antiplatelet or OAC plus aspirin regimens. OAC plus clopidogrel was ranked the most efficacious option without an increase in bleeding episodes. However, triple therapy improved the efficacy outcomes at the expense of increasing hemorrhage. For the initial short-term outcomes, OAC plus clopidogrel inconclusively reduced the risk of MACE and had a significantly lower risk of any bleeding. CONCLUSIONS: OAC plus clopidogrel may be the optimal antithrombotic therapy in patients on oral anticoagulation undergoing PCI, which has equal or better efficacy outcomes without increasing the rates of bleeding episodes. Moreover, we found initial triple therapy to be unnecessary as it increased the risk of bleeding.