Background 14-3-3η is an intracellular protein also detected in the serum and synovial fluid of patients with rheumatoid arthritis (RA). It is closely related to disease activity and anti-cyclic citrullinated peptide antibody levels. However, the main source of 14-3-3η and the mechanism of its release into the extracellular space remain unclear. Addressing these two points was the main goal of the current study. Methods The source of 14-3-3η was investigated by immunostaining RA synovial tissue. Fibroblast-like synoviocytes, CD4+ cells, and macrophages were selected as candidates among the various cell types in the synovial tissue. Phosphorylation of mixed-lineage kinase domain-like pseudokinase (MLKL) and cell death of macrophages were studied by phalloidin staining and electron microscopy after stimulation with an oxidative stress inducer (diamide) or tumour necrosis factor (TNF)-α. Extracellular 14-3-3η protein levels were examined by western blotting. Results Macrophages from the synovial tissue from RA, but not osteoarthritis, showed dense and widespread cytoplasmic staining for the 14-3-3η protein, co-localized with peptidylarginine deiminase 4. Swelling and membrane rupture of macrophages were induced by treatment with TNF-α, but not interleukin (IL) 6/soluble IL-6 receptor (sIL-6R). Increased MLKL phosphorylation followed by necroptosis was also induced in TNF-α-stimulated macrophages. Necrostatin-1, a necroptosis inhibitor, antagonized MLKL phosphorylation. High levels of 14-3-3η were detected in the culture supernatants of macrophages stimulated with diamide and TNF-α, but not IL-6/sIL-6R. Conclusions Macrophages that highly express 14-3-3η undergo TNF-α-induced necroptosis with damage to the cellular structure, resulting in the secretion of 14-3-3η into the extracellular space. The current study provides a novel mechanism for 14-3-3η level increase in the RA synovial fluid.
Background/PurposeTo evaluate biomarkers as predictors of impending erosion progression.MethodsVariables were measured at baseline and annually up to 5 years in patients with recent-onset polyarthritis treated to zero swollen joints. Erosive status was defined as ≥5 Units in Sharp/van der Heijde Erosion Score; Rapid Erosive Progression (REP) was defined as an increase ≥5 Units in Erosion Scores between consecutive visits. Generalised estimating equations (GEEs) evaluated the effect on REP of positive anticyclic citrullinated peptides (ACPAs) and/or rheumatoid factor (RF), C-reactive protein ˃8.0 mg/L (High-CRP) and 14-3-3η protein ≥0.50 ng/mL (High-14-3-3η), alone and in combinations.ResultsOut of 2155 evaluations in 749 consecutive patients, REP occurred after 186 (8.6%) visits, including 13 (2.2%) in patients recruited since 2010. Only 18/537 (3.4%; 6/411 (1.5%) in non-erosive vs 12/126 (9.5%) in patients already erosive) visits without any positive biomarker were followed by REP; at least one biomarker was positive prior to REP in 168/186 (90.3%) visits. Being positive for all four biomarkers conferred a positive predictive value (PPV) of 30.0% (RR 21.8) in patients non-erosive at the visit versus 35.5% (RR 3.07) in those already erosive. High-14-3-3η increased REP only in visits with High-CRP (eg, RR 2.5 to 3.9 when ACPA also positive) and in patients with non-erosive status (eg, RR from 4.3 to 9.4 when also High-CRP).ConclusionsAdding High-14-3-3η to positive antibodies and CRP improves prediction of impending REP. Although REP is becoming rarer, signatures of biomarkers might help to adapt treatment strategies in at-risk individuals, even those already erosive.
Background: Emerging evidence suggests that patients are increasingly willing to use digital mobile health applications for rheumatoid arthritis (RA apps). The development and diffusion of RA apps open the possibility of improved management of the disease and better physician-patient interactions. However, adoption rates among apps have been lower than hoped, and research shows that many available RA apps lack key features. There is little research exploring patient preferences for RA apps or patients' habits and preferences for app payment, which are likely key factors affecting adoption of this technology. This study seeks to understand characteristics of RA patients who have adopted RA apps, their preferences for app features, and their willingness to pay for, and experiences with app payment.Methods: Data for this study come from a 33-question online survey of patients with RA in Canada and the United States (N=30). Information on demographics, diagnosis and management of RA, current use and desired features of RA apps, and prior experience with and willingness to pay for an app was collected. Descriptive statistics are reported, and bivariate analyses (chi-square, point-biserial correlation, and ANOVA) were performed to understand relationships between variables. Results: Respondents showed a clear preference for certain app features, namely symptom tracking, scheduling appointments, and reminders. Physician recommendation for an app and patient tracking of symptoms with an app were significantly related to patient adoption of an RA app. Years since diagnosis with RA, physician recommendation for an RA app, and current use of a non-RA health tracking app were significantly related to patients' willingness to pay a subscription for an RA app. Conclusion:RA patients appear to prefer task support features in an RA app, notably symptom tracking, appointment scheduling, and reminders, over other features such as those related to dialogue support and social support. The choice of whether an RA app will be free or based on a subscription, pay-per-service, or one-time purchase model may also play a role in eventual adoption. Similarly, physician recommendation appears to influence patients' decision to use an RA app as well as their willingness to pay a subscription for an app.
Background14–3–3η is a protein that is overexpressed in serum and joint fluid of patients with rheumatoid arthritis (RA) and may represent a diagnostic biomarker for RA.ObjectivesWe assessed the prevalence and serum levels of 14–3–3η in patients with RA and with other rheumatic diseases.MethodsSerum levels of 14–3–3η were measured in 96 patients with RA, in 101 patients with other rheumatic diseases and in 66 healthy subjects. The RA group consisted of 51 patients with well-established RA who were treated with different DMARDs, and 45 patients with early untreated disease (onset of less than 1 year). The disease control group included 33 patients with systemic lupus erythematosus (SLE), 44 patients with ankylosing spondylitis (AS) and 24 psoriatic arthritis (PsA) patients. All of the sera samples were evaluated by JOINT stat 14–3–3η ELISA test kits (Augurex Life Sciences Corp.). The cut-off was defined as 0.19 ng/ml.ResultsMedian (IQR) 14–3–3η levels were significantly higher in the early RA group [0.25 ng/ml (0.075–3.11)] and in established RA patients [0.15 ng/ml (0.08–1.26)] in comparison with healthy subjects [0 ng/ml (0–0)] and disease controls: SLE [0.01 ng/ml (0–0.055)], AS [0.05 ng/ml (0–0.255)] and PsA [0.01 ng/ml (0–0.065)].The prevalence of 14–3–3η positivity in early RA patients was 58%, significantly higher than in the disease control group (SLE: 9%, p<0.001; AS: 27%, p<0.002, PsA: 12.5%, p<0.001) and in the healthy subjects group (5%, p<0.001). In established-RA patients, this prevalence was 43%, and it was significantly higher than in disease control and healthy subjects groups (p<0.05), excluding the AS group (p=0.054).ConclusionsThe concentration of 14–3–3η protein may be used to distinguish between patients with early RA and patients with other rheumatic diseases and serve as an additional biomarker in the diagnosis of RA.Disclosure of InterestO. Shovman: None declared, B. Gilburd: None declared, A. Watad: None declared, H. Amital: None declared, P. Langevitz: None declared, N. L. Bragazzi: None declared, M. Adawi: None declared, D. Pérez: None declared, G. Bornstein : None declared, M. Lidar : None declared, M. Blank: None declared, Y. Azuri: None declared, N. K. Biln Employee of: Augurex Life Sciences Corp, A. Marotta Employee of: Augurex Life Sciences Corp, Y. Shoenfeld: None declared
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