Background/Purpose: We have previously reported on a risk prediction rule for the development of rheumatoid arthritis (RA) in 374 seropositive (RF and/or ACPA) arthralgia patients, incorporating such variables as a first degree relative with RA, alcohol consumption and ACPA status. Serum 14-3-3η is a new marker that complements ACPA/RF in the diagnosis of RA. In this study, we investigated whether 14-3-3η is present in the serum of subjects prior to the onset of RA and whether its expression is useful as a predictor of RA development.

Methods: Serum 14-3-3η protein levels at study entry were measured in 40 seropositive arthralgia subjects, selected on the basis of twenty (20) subjects developing RA within 4 years from study entry, and the other half not. 14-3-3η positivity was defined as >0.19 ng/ml. Twenty-eight (28) of the 40 subjects were ACPA positive, 26 were RF positive, and 16 were positive for both markers. Contingency and logistic regression analyses were performed to determine if 14-3-3η positivity was independently associated with RA development and whether titres of ACPA, 14-3-3η and RF could strengthen its prediction.

Results: Eleven (11) of the 40 subjects were seropositive for the 14-3-3η protein, 9 (82%) of which developed RA, and of the 29 who were 14-3-3η negative, 18 (62%) did not develop RA. Similar to our findings in the larger cohort, ACPA positivity was associated with the development of RA with a Likelihood Ratio (LR) of 17.3, p < 0.01 while RF positivity was not. Contingency analysis revealed that 14-3-3η positivity was an independent predictor of RA development delivering an LR of 6.5, p = 0.01, an Odds Ratio (OR) of 7.4 p < 0.01 (95%CI, 1.3 - 40.6) and a Relative Risk (RR) of 2.2 (95%CI, 1.3 - 3.7). Consistent with previously published findings, median ACPA levels were significantly higher in 14-3-3η positive versus 14-3-3η negative subjects [312 IU/ml (IQR, 155 - 1403) versus 113 IU/ml (IQR, 1 - 735), p = 0.05]. RF titres did not differ significantly between these two groups. The predictive value of 14-3-3η positivity was strengthened through the addition of actual 14-3-3η titres yielding an OR of 17.1, p < 0.009 (95%CI, 1.9 - 660.2). Since ACPA titres were also significantly different between 14-3-3η positive and negative subjects, adding the actual ACPA titres to the model further strengthened the predictive power of 14-3-3η positivity delivering an OR of 21.5, p < 0.008 (95%CI, 2.0 - 981.2).

Conclusion: 14-3-3η expression precedes the onset of RA and its presence is strongly associated with the development of RA. The predictive power of positive 14-3-3η status was further strengthened by the addition of 14-3-3η and ACPA titres to the model. A larger study is underway to investigate 14-3-3η as a diagnostic biomarker to screen seropositive arthralgia patients for the risk of developing RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/serum-14-3-3%ce%b7-precedes-and-independently-predicts-the-development-of-ra/