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

Nathalie Carrier, Anthony Marotta, Artur J de Brum-Fernandes, Patrick Liang, Ariel Masetto, Henri A Ménard, Walter P Maksymowych, Gilles Boire, Nathalie Carrier, Anthony Marotta, Artur J de Brum-Fernandes, Patrick Liang, Ariel Masetto, Henri A Ménard, Walter P Maksymowych, Gilles Boire

Abstract

Background: Age, 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.

Methods: Clinical 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).

Results: Among 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.

Conclusions: Levels 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 registration: ClinicalTrials.gov ID: NCT00512239 . Registered August 6, 2007.

Figures

Fig. 1
Fig. 1
Simplified Disease Activity Index (SDAI) remission (a) and erosive progression (b) over 5 years according to baseline 14-3-3η positivity. General estimating equations analysis was performed to compare SDAI scores and radiographic progression over time with baseline 14-3-3η ≥0.50 ng/ml. a SDAI remission over time was significantly lower in patients with baseline 14-3-3η ≥0.50 (relative risk (RR) = 0.79 (95 % CI 0.64–0.98), p = 0.03). b Definite erosive progression (ΔErosion ≥5) over time was significantly higher in patients with baseline 14-3-3η ≥0.50 ng/ml (RR = 2.04 (95 % CI 1.53–2.70), p <0.001)
Fig. 2
Fig. 2
Radiographic progression over 5 years according to Simplified Disease Activity Index (SDAI) remission and 14-3-3η positivity. Generalized linear model analysis was performed to compare radiographic progression over time with 14-3-3η ≥0.50 ng/ml. a Relative to patients with lower 14-3-3η levels, erosive damage progression (ΔErosion) was significantly higher in patients with 14-3-3η ≥0.50 ng/ml at 18 months, whether the patients were in SDAI remission (p = 0.002) or had active SDAI levels at 18 months (p <0.001). b Relative to patients with lower 14-3-3η levels, yearly erosive damage progression (ΔErosion) was significantly higher in patients with 14-3-3η ≥0.50 ng/ml at the previous visit, whether the patients were already in SDAI remission (p = 0.0079) or had active SDAI levels (p <0.001) at the previous visit. SEM standard error of the mean

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Source: PubMed

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