Background/Purpose: The focus of RA management is increasingly towards early detection and treatment. While newly-diagnosed patients will benefit from treatment decisions based on more robust methods of predicting disease severity, identifying arthralgia patients at increased risk of RA development will enable interventional studies focused on prevention. We recently published a prediction rule for the development of RA in seropositive arthralgia patients. Serum 14-3-3η is a novel protein biomarker that is useful for RA diagnosis and is involved in the joint damage process. This study evaluated 548 patients to determine if 14-3-3η may predict (a) RA development in arthralgia patients and (b) radiographic progression in early RA.

Methods: 148 consecutive patients of whom 44 (30%) developed RA within 5 years and 104 that did not, were selected from the prospective Reade cohort of ACPA and/or RF positive arthralgia patients. Age and gender did not differ between the groups. 400 early RA patients, by 2010 ACR/EULAR criteria, from a prospective Reade cohort were included (4 months median symptom duration, 5 yrs follow-up, mean age 55, 73% female). Frozen sera from baseline were tested on a blinded basis using the Augurex 14-3-3η ELISA (positive ≥0.19 ng/ml). 2-tailed t-tests and Mann-Whitney U-tests were used to assess group differences. Contingency analyses and multivariate regressions were used to identify serologic variables associated with RA development and radiographic progression (ΔSHS ≥ 1.0 and ≥ 3.0) over 5 yrs.

Results: Prediction of RA. Median 14-3-3η levels were significantly higher in the arthralgia group that developed RA, p<0.004. 14-3-3η positive individuals, by contingency analysis had a significantly higher likelihood of developing RA, LR=5.7. Univariate analysis returned baseline 14-3-3η levels (p<0.03) and ACPA (p<0.03), but not RF as associated with RA development. In multivariate analysis, 14-3-3η was an independent predictor of RA (p<0.04) when combined with ACPA and other clinical variables.

Prediction of radiographic progression. 268 (67%) of the early RA patients were 14-3-3η positive. Median baseline levels of 14-3-3η (p<0.006) and RF (p<0.03), but not ACPA, were higher in patients that progressed by yr 5. Over the 5 yrs, 14-3-3η positive patients had significantly higher median ΔSHS than the negatives, 3.0 vs 1.5, p<0.005. By contingency analysis, the association between 14-3-3η positivity and radiographic progression at yrs 1, 3 and 5 delivered LRs from 3.8 – 6.8. ACPA and RF positivity were also significantly associated with damage progression. 

Conclusion: Serum 14-3-3η protein is an independent predictor of RA development in arthralgia patients and its baseline expression in early RA predicts radiographic changes. 14-3-3η is being further investigated to determine how it may be added to current clinical and serological measures to identify high risk patients for early intervention to improve outcomes.