Serum levels of 14-3-3η protein supplement C-reactive protein and rheumatoid arthritis-associated antibodies to predict clinical and radiographic outcomes in a prospective cohort of patients with recent-onset inflammatory polyarthritis

Abstract

BackgroundAge, C-Reactive Protein (CRP) and autoantibodies (Abs) are associated with worse prognosis in patients with recent-onset inflammatory polyarthritis (EPA). Serum 14-3-3η protein is a joint-derived biomarker that up-regulates cytokines and enzymes that perpetuate local and systemic inflammation and may contribute to joint damage. Our objective was to evaluate, over a 5-year prospective period of observation, the additional prognostic potential of serum 14-3-3η protein in EPA patients.MethodsClinical variables, serum and radiographs (scored according to the Sharp/van der Heijde (SvH) method) were collected serially. Relationships between serum 14-3-3η protein and other biomarkers were computed with Spearman correlations. Outcomes were Simple Disease Activity Index (SDAI) scores and joint damage progression: ΔSvH for SvH score and ΔErosion for its Erosive component. The additional predictive contribution of 14-3-3η was defined using generalized estimating equations (GEE) and generalized linear mixed models (GLMM).ResultsAmong 331 patients, baseline 14-3-3η was ≥0.19 and ≥0.50 ng/ml in 153 (46.2 %) and 119 (36.0 %), respectively; CRP was >8.0 mg/L in 207 (62.5 %), and at least one Ab (Rheumatoid Factor, anti-CCP2 or anti-Sa/citrullinated vimentin) was positive in 170 (51.5 %). Elevated 14-3-3η levels moderately correlated with positive Abs, but not with elevated CRP. Baseline 14-3-3η ≥0.19 ng/ml was associated with more radiographic progression over 5 years. The optimal levels of baseline 14-3-3η to predict radiographic progression was defined by ROC curves at 0.50 ng/ml. Levels of 14-3-3η ≥0.50 ng/ml at baseline were associated with lower likelihoods of ever reaching SDAI remission (RR 0.79 (95 % CI 0.64–0.98), p = 0.03) and higher subsequent progression of Total and Erosion SvH scores. Elevated levels of 14-3-3η during follow-up also predicted higher subsequent progression, even in patients in SDAI remission. Decreases of 14-3-3η levels by at least 0.76 ng/ml and reversion to negative during follow-up associated with less subsequent radiographic progression. In multivariate models, elevated 14-3-3η interacted with positive Abs, elevated CRP and older age to predict subsequent radiographic progression.ConclusionsLevels of 14-3-3η protein ≥0.50 ng/ml predict poorer clinical and radiographic outcomes in EPA, both at baseline and after initiation of treatment, even in SDAI remitters. 14-3-3η, CRP, age and Abs represent independent predictors of subsequent joint damage.Trial registrationClinicalTrials.gov ID: NCT00512239. Registered August 6, 2007.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-0935-z) contains supplementary material, which is available to authorized users.

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

“…6 We also observed that baseline 14-3-3η levels, CRP levels, age and antibodies in recent-onset polyarthritis represented independent predictors of subsequent joint damage over 5 years. 6…”

“…Positive 14-3-3η was defined at ≥0.19 ng/mL; high positive (High-14-3-3η) was defined at ≥0.50 ng/mL. 6…”

“…4 When added to high C-reactive protein (High-CRP; ˃8.0 mg/L), elevated (≥0.19 ng/mL) 14-3-3η serum levels identified significantly more RA patients with radiographic progression. 5 6 Patients who reverted from positive to negative 14-3-3η levels had better clinical response than patients who remained positive at 1 year. 5 We previously found that a higher 14-3-3η cut-off at 0.50 ng/mL was optimal to predict more adverse clinical and radiographic outcomes in early RA.…”

Is It Time to Banish Composite Measures for Remission in Rheumatoid Arthritis?

“…Perhaps if defining remission in RA as 0 swollen joints is too difficult, then a biomarker could be a surrogate instead, such as the multibiomarker disease activity score (MBDA) or 14‐3‐3η protein . These measures correlate well with disease activity, and the MBDA may perform better than the CRP level or DAS28 score for radiograph progression , and even if in Simplified Disease Activity Index remission the 14‐3‐3η enzyme‐linked immunosorbent assay levels can predict radiographic progression , they are expensive and have not been tested to determine whether they provide added value to the physician global assessment or the actual SJC. The subspecialty of rheumatology should continue to use the joint assessment with the physical examination to define active RA and remission in RA.…”

Prevalence and Significance of Serum 14-3-3η(eta) in Juvenile Idiopathic Arthritis

“…In addition, patients with early RA and detectable 14-3-3η at baseline had more erosive disease at 5 years compared to those with normal 14-3-3η levels at baseline [11]. Further, patients with adult RA in apparent clinical remission after 18 months of therapy had worse Sharp scores at 30 months if their 18-month 14-3-3η level was ≥ 0.5 ng/mL [13]. Additionally, psoriatic arthritis patients have been reported to have more erosive disease at a lower level of 14-3-3η compared to RA patients [8].…”