Dysregulation of platelet serotonin, 14-3-3, and GPIX in sudden infant death syndrome.

Sudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant mortality, but the underlying cause(s) are unclear. A subset of SIDS infants has abnormalities in the neurotransmitter, serotonin (5-hydroxytryptamine [5-HT]) and the adaptor molecule, 14-3-3 pathways in regions of the brain involved in gasping, response to hypoxia, and arousal. To evaluate our hypothesis that SIDS is, at least in part, a multi-organ dysregulation of 5-HT, we examined whether blood platelets, which have 5-HT and 14-3-3 signaling pathways similar to brain neurons, are abnormal in SIDS. We also studied platelet surface glycoprotein IX (GPIX), a cell adhesion receptor which is physically linked to 14-3-3. In infants dying of SIDS compared to infants dying of known causes, we found significantly higher intra-platelet 5-HT and 14-3-3 and lower platelet surface GPIX. Serum and plasma 5-HT were also elevated in SIDS compared to controls. The presence in SIDS of both platelet and brainstem 5-HT and 14-3-3 abnormalities suggests a global dysregulation of these pathways and the potential for platelets to be used as a model system to study 5-HT and 14-3-3 interactions in SIDS. Platelet and serum biomarkers may aid in the forensic determination of SIDS and have the potential to be predictive of SIDS risk in living infants.

Diagnostic and Prognostic Value of Plasma GFAP in Sporadic Creutzfeldt-Jakob Disease in the Clinical Setting of Rapidly Progressive Dementia.

The diagnostic and prognostic value of plasma glial fibrillary acidic protein (pl-GFAP) in sporadic Creutzfeldt-Jakob disease (sCJD) has never been assessed in the clinical setting of rapidly progressive dementia (RPD). Using commercially available immunoassays, we assayed the plasma levels of GFAP, tau (pl-tau), and neurofilament light chain (pl-NfL) and the CSF total tau (t-tau), 14-3-3, NfL, phospho-tau181 (p-tau), and amyloid-beta isoforms 42 (Aß42) and 40 (Aß40) in sCJD (n = 132) and non-prion RPD (np-RPD) (n = 94) patients, and healthy controls (HC) (n = 54). We also measured the CSF GFAP in 67 sCJD patients. Pl-GFAP was significantly elevated in the sCJD compared to the np-RPD and HC groups and affected by the sCJD subtype. Its diagnostic accuracy (area under the curve (AUC) 0.760) in discriminating sCJD from np-RPD was higher than the plasma and CSF NfL (AUCs of 0.596 and 0.663) but inferior to the 14-3-3, t-tau, and pl-tau (AUCs of 0.875, 0.918, and 0.805). Pl-GFAP showed no association with sCJD survival after adjusting for known prognostic factors. Additionally, pl-GFAP levels were associated with 14-3-3, pl-tau, and pl-NfL but not with CSF GFAP, Aß42/Aß40, and p-tau. The diagnostic and prognostic value of pl-GFAP is inferior to established neurodegeneration biomarkers. Nonetheless, pl-GFAP noninvasively detects neuroinflammation and neurodegeneration in sCJD, warranting potential applications in disease monitoring.

Prospective Role of PAK6 and 14-3-3γ as Biomarkers for Parkinson's Disease.

Background: Parkinson's disease is a progressive neurodegenerative disorder mainly distinguished by sporadic etiology, although a genetic component is also well established. Variants in the LRRK2 gene are associated with both familiar and sporadic disease. We have previously shown that PAK6 and 14-3-3γ protein interact with and regulate the activity of LRRK2. Objective: The aim of this study is to quantify PAK6 and 14-3-3γ in plasma as reliable biomarkers for the diagnosis of both sporadic and LRRK2-linked Parkinson's disease. Methods: After an initial quantification of PAK6 and 14-3-3γ expression by means of Western blot in post-mortem human brains, we verified the presence of the two proteins in plasma by using quantitative ELISA tests. We analyzed samples obtained from 39 healthy subjects, 40 patients with sporadic Parkinson's disease, 50 LRRK2-G2019S non-manifesting carriers and 31 patients with LRRK2-G2019S Parkinson's disease. Results: The amount of PAK6 and 14-3-3γ is significantly different in patients with Parkinson's disease compared to healthy subjects. Moreover, the amount of PAK6 also varies with the presence of the G2019S mutation in the LRRK2 gene. Although the generalized linear models show a low association between the presence of Parkinson's disease and PAK6, the kinase could be added in a broader panel of biomarkers for the diagnosis of Parkinson's disease. Conclusions: Changes of PAK6 and 14-3-3γ amount in plasma represent a shared readout for patients affected by sporadic and LRRK2-linked Parkinson's disease. Overall, they can contribute to the establishment of an extended panel of biomarkers for the diagnosis of Parkinson's disease.

Serum stratifin and presepsin as candidate biomarkers for early detection of COVID-19 disease progression.

The prognosis of patients with severe cases of COVID-19 is poor; thus, biomarkers for earlier prediction of COVID-19 progression are vital. We measured levels of five lung injury-related biomarkers, SP-D, KL-6, presepsin, kallistatin and stratifin, in serum samples collected serially during hospitalization from 31 patients with mild/moderate or severe/critical COVID-19 pneumonia, and their predictive performances were compared. Like the previously reported presepsin, a new biomarker candidate, stratifin, was significantly elevated with the onset of severe or critical symptoms in COVID-19 patients and decreased with symptom improvement. Notably, changes in stratifin and presepsin levels were distinctly earlier than those in SP-D, KL-6 and even SpO2/FiO2 values. Furthermore, serum levels of these biomarkers were significantly higher at the pre-severe stage (before the start of oxygen support) of patients who eventually advanced to severe/critical stages than in the patients who remained at the mild/moderate stage. These results were confirmed in an independent cohort, including 71 mild/moderate and 14 severe/critical patients, for whom the performance of stratifin and presepsin in discriminating between mild/moderate and pre-severe conditions of COVID-19 patients was superior to that of the SpO2/FiO2 ratio. Therefore, we concluded that stratifin and presepsin could be used as prognostic biomarkers for severe COVID-19 progression.

Prevalence and significance of serum 14-3-3η in juvenile idiopathic arthritis.

BACKGROUND: Prompt diagnosis of juvenile idiopathic arthritis (JIA) is important to avoid long term complications. Elevated serum 14-3-3η levels improve the diagnostic sensitivity of rheumatoid factor (RF) and cyclic citrullinated peptide (CCP) antibody in adult rheumatoid arthritis (RA), and have been associated with more severe phenotype. We investigated the prevalence and clinical significance of serum 14-3-3η in different types of JIA. METHODS: JIA patients (n = 151) followed by the Pediatric Rheumatology Core at Children's Hospital of Los Angeles were categorized into 5 groups: polyarticular JIA RF+ (PJIA RF+; n = 39), PJIA RF- (n = 39), psoriatic arthritis (PsA; n = 19), enthesitis-related arthritis (ERA; n = 18), and oligoarticular JIA (OJIA [control group]; n = 36). RF, CCP antibody, and 14-3-3η were measured for all patients. 14-3-3η serum levels > 0.2 ng/mL were considered positive. Disease activity was assessed by the Juvenile Arthritis Disease Activity Score-71 (JADAS-71). RESULTS: Elevated 14-3-3η levels were detected in 34/151 (23%) patients, and across all groups tested. Most patients with 14-3-3η had titers ≥4 times above the cutoff value. The majority (22, 65%) of 14-3-3η-positive patients were also positive for RF or CCP antibodies, 16 (47%) were positive for all 3, and 12 (35%) were single-positive for 14-3-3η. The highest prevalence of 14-3-3η was in PJIA RF+ patients (49%), followed by OJIA (22%). Positivity for 14-3-3η was not significantly associated with disease activity or age at diagnosis. CONCLUSION: Serum 14-3-3η can be detected in all forms of JIA tested but appears to be most common in PJIA RF+. 14-3-3η does not appear to correlate with disease activity in JIA.

Comparison of Serum Levels of 14-3-3 ETA Proteins between Rheumatoid Arthritis, Osteoarthritis and Normal Controls.

14-3-3 ETA protein, a joint-derived biomarker that up-regulates inflammatory cytokines which enhances local and systemic inflammation and may lead to destructive changes in joints, is thought to be a good diagnostic marker for early RA. To assess the usefulness of serum levels of 14-3-3 ETA in the diagnosis of RA. This is a case-control study which involved 3 groups: group 1 included 30 RA patients, group 2 included 30 primary osteoarthritis patients and group 3 included 30 healthy controls. All study subjects were assessed using laboratory investigations as CBC, ESR, CRP, RF, ACPA as well as serum levels of 14-3-3 ETA protein which were measured through ELISA technique. Mean ± SD levels of 14-3-3 ETA were significantly higher among RA compared to OA and control groups (0.7(0.5), 0.2 (0.1) and 0.3(0.1) ng/ml, respectively) with a sensitivity of 79.3%, specificity of 81.7%, positive predicted value of 86% and negative predicted value of 81%. 14-3-3 ETA also had high diagnostic OR (1478.04). A statistically significant correlation (r= 0.259) was found between serum levels of 14-3-3 ETA and ESR. In conclusion, 14-3-3 ETA is a novel marker for RA that should be used in conjunction with RF and ACPA for diagnosis of the disease.

Diagnostic accuracy of 14-3-3 η protein in rheumatoid arthritis: A meta-analysis.

AIM: To evaluate the overall diagnostic performance of 14-3-3 η protein in patients with rheumatoid arthritis (RA). METHODS: PubMed, EMBASE, and Web of Science were searched to acquire eligible studies. Articles published in English before 20 February 2020 were included. Quality Assessment of Diagnostic Accuracy Studies 2 was used to evaluate the risk of bias and application concern of the included articles. Pooled analysis of diagnostic indicators of 14-3-3 η protein for RA was conducted by using a random effects model. Subgroup analysis was used to explore the sources of heterogeneity. Deeks' funnel plot asymmetry test was used to evaluate for the presence of publication bias. RESULTS: A total of 13 studies (1554 positive and 1934 negative participants) were included. The pooled sensitivity and specificity were 0.73 (95% CI 0.71-0.75) and 0.88 (95% CI 0.87-0.90), respectively. The pooled positive/negative likelihood were 5.98 (95% CI 4.39-8.14) and 0.28 (95% CI 0.21-0.37), respectively. In addition, the pooled diagnostic odds ratio was 23.48 (95% CI 13.76-40.08) and the area under curve was 0.9245. The results of subgroup analysis indicated that ethnicity and control group might be the source of heterogeneity. The results of sensitivity analysis were stable. No significant publication bias was found. CONCLUSIONS: The current evidence indicated that 14-3-3 η protein has moderate accuracy for the diagnosis of RA.

Comparison between plasma and cerebrospinal fluid biomarkers for the early diagnosis and association with survival in prion disease.

OBJECTIVE: To compare the diagnostic accuracy and the prognostic value of blood and cerebrospinal fluid (CSF) tests across prion disease subtypes. METHODS: We used a single-molecule immunoassay to measure tau and neurofilament light chain (NfL) protein levels in the plasma and assessed CSF total(t)-tau, NfL and protein 14-3-3 levels in patients with prion disease (n=336), non-prion rapidly progressive dementias (n=106) and non-neurodegenerative controls (n=37). We then evaluated each plasma and CSF marker for diagnosis and their association with survival, taking into account the disease subtype, which is a strong independent prognostic factor in prion disease. RESULTS: Plasma tau and NfL concentrations were higher in patients with prion disease than in non-neurodegenerative controls and non-prion rapidly progressive dementias. Plasma tau showed higher diagnostic value than plasma NfL, but a lower accuracy than the CSF proteins t-tau and 14-3-3. In the whole prion cohort, both plasma (tau and NfL) and CSF (t-tau, 14-3-3 and NfL) markers were significantly associated with survival and showed similar prognostic values. However, the intrasubtype analysis revealed that only CSF t-tau in sporadic Creutzfeldt-Jakob disease (sCJD) MM(V)1, plasma tau and CSF t-tau in sCJD VV2, and plasma NfL in slowly progressive prion diseases were significantly associated with survival after accounting for covariates. CONCLUSIONS: Plasma markers have lower diagnostic accuracy than CSF biomarkers. Plasma tau and NfL and CSF t-tau are significantly associated with survival in prion disease in a subtype-specific manner and can be used to improve clinical trial stratification and clinical care.

Heat shock protein 90 alpha and 14-3-3η in postmenopausal osteoporotic rats with varying levels of serum FSH.

PURPOSE: This study compared the severity of osteoporosis and screened differentially expressed proteins in postmenopausal osteoporotic rats with varying levels of serum follicle stimulating hormone (FSH). METHODS: Thirty-six Sprague Dawley female rats were divided into four groups: sham operation (sham) group, ovariectomy (OVX) group, FSH and ovariectomy (OVX + FSH) group, and Leuprorelin (LE) and ovariectomy group (OVX + LE). Body weight, serum estradiol, FSH, tartrate-resistant acid phosphatase, alkaline phosphatase, and bone mineral density were measured. We randomly selected six rats each from the OVX and OVX + FSH groups to detect differentially expressed proteins by data-independent acquisition, and we verified the results in the remaining six rats by enzyme-linked immunosorbent assay (ELISA). RESULTS: Nineteen proteins were upregulated and 36 proteins were downregulated in the OVX + FSH group. The expression of heat shock protein 90 alpha (Hsp90α) and 14-3-3η protein was significantly different between the OVX and OVX + FSH groups, and both were linearly correlated with bone trabecular area. Results were verified by ELISA and were found to be consistent with the results of data-independent acquisition. DISCUSSION: In rats with high serum FSH, expression of Hsp90α protein was increased and expression of 14-3-3η protein was decreased. Both changes in protein expression were strongly correlated with bone trabecular area.

Impending radiographic erosive progression over the following year in a cohort of consecutive patients with inflammatory polyarthritis: prediction by serum biomarkers.

BACKGROUND/PURPOSE: To evaluate biomarkers as predictors of impending erosion progression. METHODS: Variables 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. RESULTS: Out 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). CONCLUSIONS: Adding 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.

14-3-3η Protein in Rheumatoid Arthritis: Promising Diagnostic Marker and Independent Risk Factor for Osteoporosis.

BACKGROUND: Early identification and disease monitoring are challenges facing rheumatologists in the management of rheumatoid arthritis (RA). METHODS: We utilized enzyme-linked immunosorbent assay (ELISA) to determine 14-3-3η and anticyclic citrullinated peptide antibody (anti-CCP) levels, with rheumatoid factor (RF) level detected by rate nephelometry. The diagnostic value of each index was determined via receiver operating characteristic (ROC) curve, and the association between 14-3-3η and osteoporosis was assessed using multiple logistic regression analysis. RESULTS: Serum levels of 14-3-3η were 3.26 ng per mL in patients with RA. These levels were helpful in identifying patients with the disease, with the area under the curve (AUC) being 0.879 and 0.853, respectively, from all healthy control individuals and patients with RA. Combining 14-3-3η with RF or anti-CCP increased the diagnostic rate. Logistic regression analysis identified 14-3-3η as an independent risk factor for RA-related osteoporosis (odds ratio [OR], 1.503; 95% confidence interval [CI], 1.116-2.025; P <.01). CONCLUSIONS: Serum 14-3-3η detection by itself or combined with other serum indices was helpful in differentiating patients with RA. Also, it was a promising biomarker for disease monitoring in RA.

14-3-3η Protein in serum and synovial fluid correlates with radiographic damage and progression in a longitudinal evaluation of patients with established rheumatoid arthritis.

Objectives: The aim of the study is to examine the association between 14-3-3η protein levels in both serum and synovial fluid (SF) with various parameters in a longitudinal cohort of patients with established rheumatoid arthritis (RA).Methods: Serum and SF samples were obtained from RA patients and 14-3-3η levels were measured. Radiological damage and progression were evaluated using Sharp/van der Heijde score (SHS) at study entry and at 2-years follow-up.Results: A total of 39 RA patients were included with a mean disease duration of 9.6 ± 8 years. Levels of 14-3-3η were two-fold higher in SF than in serum (mean of 3.7 versus 1.7 ng/mL, respectively). While no significant association was found between 14-3-3η levels with disease activity or other laboratory assessments, both serum and SF 14-3-3η levels positively correlated with radiographic damage at baseline (SHS; p < .001). SF, but not serum, 14-3-3η levels correlated with absolute progression (p < .03).Conclusion: 14-3-3η levels are significantly higher in RA SF than in serum in an established RA cohort. Serum and SF 14-3-3η levels correlate with radiographic damage at baseline and at 2-years follow-up. This study further substantiates the utility of 14-3-3η as a biomarker for mechanistic joint damage in established RA.

Diagnostic performance of 14-3-3η and anti-carbamylated protein antibodies in Rheumatoid Arthritis in Han population of Northern China.

OBJECTIVES: As we already know, Rheumatoid arthritis (RA) cannot be excluded when the rheumatoid factor (RF) or anti-cyclic citrullinated peptide antibody (anti-CCP) is negative. Here, we determined the application value of 14-3-3η protein, anti-carbamylated proteins antibodies (anti-CarP), as well as their potential role to diagnose RA together with RF or anti-CCP. METHOD: Serum levels of anti-CCP, RF, 14-3-3η and anti-CarP antibodies were detected in 291 RA patients, 223 patients with autoimmune diseases except RA, and 156 healthy subjects recruited from Han population of Northern China. We examined the differences in the levels of these indicators among groups and compared the correlations between any two of the indicators. At the same time, a total of 12 testing strategies were established for comparison to maximize the diagnostic value. RESULT: The levels of RF, anti-CCP, anti-CarP and 14-3-3η were significantly higher in RA patients (12.5;[9.36-15.7], 30.7;[25.7-35.6], 1.90;[1.70-2.01], 15.8;[10.8-20.8], respectively) compared with either interference-control group (1.24;[1.07-1.41], 0.64;[0.42-0.86], 0.51;[0.46-0.57], 0.33;[0.23-0.44], respectively) (p < 0.0001) or healthy-control group (1.03;[0.99-1.08], 0.49;[0.38-0.59], 0.28;[0.21-0.35], 0.55;[0.27-0.85], respectively) (p < 0.0001). Among all 12 detection strategies, the YI and κ value of a novel strategy that either double-positive of any 2 markers or single-positive of anti-CCP can be diagnosed as RA had the highest diagnostic value. CONCLUSION: The results of our study demonstrated that in Han population of Northern China, anti-CarP antibodies and 14-3-3η protein can be treated as valuable indicators of RA, especially when combined with RF and anti-CCP, the detection value is maximized.

Importance of 14-3-3eta, anti-CarP, and anti-Sa in the diagnosis of seronegative rheumatoid arthritis

Background/aim: Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation. The study aimed to assess serum 14-3-3eta, anti-CarP, and anti-Sa in seronegative RA (SNRA) patients who were treatment-naïve as well as in healthy subjects. This is the first study in the literature to examine these autoantibodies together in SNRA patients. Materials and methods: Forty-five treatment-naïve SNRA patients and 45 healthy subjects were recruited. Drugs change the levels of autoantibodies; therefore, patients who took any medication had been excluded from our study. Anti-carbamylated protein, anti-Sa, and 14-3-3eta were measured by using three different ELISA kits. Results: Median serum concentration of healthy controls in 14-3-3eta was 0.02 (0.02­0.27) ng/mL. Median serum concentration of SNRA patients in 14-3-3eta was 1.00 (0.48­1.28) ng/mL. Data were analyzed with Mann­Whitney U tests; the P-value was <0.001 in 14-3-3eta. Receiver operating characteristic (ROC) curve analysis showed that 14-3-3eta in SNR compared to healthy controls had a significant (P < 0.001) area under the curve (AUC) of 0.90 (95% confidence interval, 0.83­0.96). At a cutoff of ≥0.33 ng/mL, the ROC curve yielded a sensitivity of 88.9%, a specificity of 82.2%, a positive predictive value of 83.3%, and a negative predictive value of 88.1%. Conclusion: We found that 14-3-3eta can be used as a diagnostic marker in SNRA.

Evaluation of Serum Protein 14-3-3η (Eta) as a Novel Biomarker for Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is one of the most common systemic autoimmune diseases. New markers are needed for early diagnosis of RA as seronegativity in both early and established RA remains a major limitation of both anticitrullinated protein antibodies (ACPA) and rheumatoid factor (RF). The 14-3-3η protein may represent a novel biomarker for the detection of RA. We evaluated the diagnostic performance of serum 14-3-3η protein in early and established cases of rheumatoid arthritis and we compared the diagnostic accuracy of it with those of the well-known RA markers (e.g. RF and ACPA). Sera from 50 patients with RA (20 early and 30 established) based on the 2010 ACR / EULAR Rheumatoid Arthritis Classification Criteria, 15 patients with non-RA arthritis as diseases control group (8 patients with OA and 7 patients with SLE) and 14 healthy controls were enrolled in the study. Serum RF was determined by latex, ACPA and 14-3-3η protein were determined by ELISA. Serum 14-3-3η protein levels in patients with RA were significantly higher (P=0.001*) as compared to healthy individuals. For serum 14-3-3η diagnostic accuracy in RA; Receiver operating characteristic curves (ROC) analysis comparing patient with RA with healthy control showed AUC (0.916) at optimum cutoff of > 2.5ng/mL, and a sensitivity of 100%, a specificity of 78.57%, a PPV of 94.3, and an NPV of 100. No significant difference in 14-3-3η protein serum levels was found between early and established RA groups. It was positive in 100% of early and established RA patients who were seronegative for RF and ACPA. It is concluded that, 14-3-3η protein could improve the sensitivity of RA diagnosis and cover the shortage of detection of RF and ACPA in RA patients.

Diagnostic values of serum IL-10 and IL-17 in rheumatoid arthritis and their correlation with serum 14-3-3η protein.

OBJECTIVE: This study aimed to investigate the diagnostic values of serum IL-10 and IL-17 in rheumatoid arthritis (RA) and their correlation with serum protein. PATIENTS AND METHODS: A retrospective analysis was performed on 116 RA patients admitted to the Yantaishan Hospital (the RA group) and 116 healthy subjects (the control group). Enzyme-linked immunosorbent assay was used to detect the expression levels of serum interleukin (IL)-10, IL-17 and 14-3-3η protein. Pearson analysis was performed to analyze the correlation between the expression levels of serum IL-10, IL-17 and 14-3-3η protein of patients in the RA group, and ROC curve analysis was conducted to measure the diagnostic values of IL-10, IL-17 and their combination in RA. RESULTS: Patients in the RA group had significantly lower serum IL-10 level and markedly higher IL-17 and 14-3-3η protein levels than those in the control group (p<0.001). Serum IL-10 level was negatively correlated with 14-3-3η protein level in RA patients (r=-0.582, p<0.001). Serum IL-17 level was positively correlated with 14-3-3η protein level in RA patients (r=0.482, p<0.001). Serum IL-10 level was negatively correlated with IL-17 level in RA patients (r=-0.468, p<0.001). The AUC of IL-10 for diagnosing RA was 0.671, with a 95% confidence interval of 0.602-0.741 and a cut-off value of 87.315. The AUC of IL-17 for diagnosing RA was 0.856, with a 95% confidence interval of 0.807-0.905 and a cut-off value of 87.844. The AUC of IL-10 combined with IL-17 for diagnosing RA was 0.887. CONCLUSIONS: RA patients had remarkably lower serum IL-10 level and significantly higher IL-17 and 14-3-3η protein levels than healthy people. IL-17 has better sensitivity and specificity than IL-10 for diagnosing RA. IL-10 combined with IL-17 is beneficial to improve the diagnostic level of RA, which provides the reference for the diagnosis, treatment and pathogenesis of RA.

Serum 14-3-3η Could Improve the Diagnostic Rate of Rheumatoid Arthritis and Correlates to Disease Activity.

OBJECTIVES: Serum 14-3-3η is a novel joint-derived proinflammatory mediator associated with rheumatoid arthritis (RA). This study aimed to evaluate the diagnostic capacity of serum 14-3-3η and its correlation with clinical variables in patients with RA. METHODS: A total of 94 patients with RA and 80 age- and sex-matched controls, including 40 healthy subjects, were included. Serum 14-3-3η levels were assessed by quantitative enzyme-linked immunosorbent assay. Receiver-operating characteristic (ROC) curves analysis was used to determine the sensitivity and specificity of 14-3-3η. Spearman's rank correlation coefficient was used to assess the relationship between 14-3-3η and other clinical measures in patients with RA. RESULTS: Median (interquartile range) of serum 14-3-3η concentration (ng/ml) in RA patients (2.34 [1.56-3.39]) was significantly higher than that in healthy subjects (0.17[0.11-0.30]) and disease controls (1.66[1.21-2.74]; P<0.05). ROC curve analysis comparing patients with RA with all controls demonstrated a significant (P<0.001) area under the curve (AUC) of 0.81 (95% confidence interval: 0.74-0.88). At a cutoff of 1.44 ng/mL, the ROC curve yielded a sensitivity of 78.7% and specificity of 73.8%. The sensitivity of anti-citrullinated protein antibody (ACPA) and rheumatoid factor (RF) were 84.0% and 72.3%, respectively. Adding 14-3-3η to ACPA and/or RF discriminated more than 96% of patients with RA. The positive rate of at least one of the three markers was up to 99%, with a specificity of about 70%. The results of correlation analyses revealed that serum levels of 14-3-3η protein positively correlated with C-reactive protein (r=0.250, P<0.05), erythrocyte sedimentation rate (r=0.294, P<0.01), and 28-joint disease activity score (r=0.275, P<0.05) in patients with RA. CONCLUSIONS: 14-3-3η protein is a novel marker that can apparently enhance the detection rate of patients with RA. The level of serum 14-3-3η protein correlates to some degree with disease activity.

Decrease in 14-3-3η protein levels is correlated with improvement in disease activity in patients with rheumatoid arthritis treated with Tofacitinib.

14-3-3η protein is a proinflammatory mediator that may represent a novel diagnostic and prognostic biomarker for rheumatoid arthritis (RA). We assessed the correlation between changes in serum 14-3-3η levels and changes in clinical disease activity measures in RA patients treated with Tofacitinib (TOF). Paired serum samples from 35 patients with RA were obtained at baseline and 5 months after the initiation of treatment with TOF. The levels of 14-3-3η were measured by JOINT stat 14-3-3η ELISA test kits (Augurex Life Sciences Corp.). The cut-off was defined as 0.19 ng/ml. 14-3-3η positivity was found in 57% of the patients at baseline and in 37% of the patients after 5 months of treatment. Mean ± SD baseline 14-3-3η levels [4.92 ± 8.86 ng/ml] were significantly higher (p < 0.005) than 14-3-3η levels following treatment [1.97 ± 4.59 ng/ml]. A statistically significant improvement (p < 0.001) of CDAI, SDAI, DAS4ESR and DAS4CRP was achieved after 5 month of treatment. Decrease in 14-3-3η protein levels was highly correlated with improvement in DAS4ESR (r = 0.50, p < 0.01), DAS4CRP (r = 0.46, p < 0.01) and ESR (r = 0.36, p = 0.03) and moderately correlated with improvement in CDAI (r = 0.32, p = 0.065) and SDAI (r = 0.33, p = 0.051). The correlation between decrease in 14-3-3η levels and improvement in DAS4ESR remained significant in a partial correlation analysis controlling for ESR (r = 0.39, p = 0.02). This study demonstrates that in RA patients who were treated with TOF, decrease in 14-3-3η levels is correlated with improvement in clinical disease activity parameters. The 14-3-3η protein may serve as an objective biomarker for monitoring of TOF therapy response.

14-3-3η protein: a promising biomarker for rheumatoid arthritis.

Effective management of rheumatoid arthritis (RA) depends on early identification followed by timely invention and proper monitoring of treatment responses which remain challenges facing rheumatologists for lacking biomarkers of high sensitivity and specificity. 14-3-3η has been reported to be a novel RA-related biomarker inducing the expression of multiple factors mediating the pathogenesis of RA, and increasing the diagnostic capture when combined with rheumatoid factor and anticyclic citrullinated peptide antibody. Besides, elevated serum 14-3-3η was relevant to more serious joint erosion and worse therapy outcomes. Here, we summarized the emerging knowledge regarding the roles 14-3-3η plays in RA and its clinical implications as diagnostic, prognostic and therapeutic response surrogate as well as potential drug target for RA.

Clinical significance of detecting HLA-DR, 14-3-3η protein and d-dimer in the diagnosis of rheumatoid arthritis.

AIM: To investigate the clinical significance of detecting several biomarkers collectively in the diagnosis of rheumatoid arthritis (RA). METHODS: 128 RA patients, 174 non-RA patients and 80 healthy controls were enrolled. HLA-DR4 and HLA-DR53 were detected by the PCR-SSP method, 14-3-3η protein, anti-CCP and anti-Sa were detected by ELISA and DD was detected by latex immunoturbidimetric assay. RESULTS: The positive rates of HLA-DR4, HLA-DR53, 14-3-3η protein, anti-CCP and anti-Sa were obviously higher in the RA group (43.8, 38.3, 51.6, 80 and 40.6%, respectively); anti-CCP was of highest sensitivity (79.68%), highest specificity (97.5%) and Youden index (0.77). The AUC of 14-3-3η protein, DD, anti-CCP, anti-Sa were 0.813, 0.859, 0.930, 0.861, respectively. CONCLUSION: All biomarkers were strongly correlated risk factors for RA; the combination of multiple biomarkers might be of help for diagnostic and therapeutic strategies in RA of recent onset.