Background 14-3-3eta (η) is a mechanistic biomarker that is useful in RA diagnosis. We have previously reported that its plasma expression precedes and independently predicts RA development in arthralgia subjects. 14-3-3η titres further improve the predictive value of variables such as ACPA, number of painful joints and alcohol non-use, which are independently associated with RA development.
Objectives To determine whether higher 14-3-3η serum cut-off informs a higher likelihood of RA development in arthralgia patients.
Methods 14-3-3η plasma levels were measured in 148 consecutive arthralgia patients of whom 44 (30%) developed RA [median time to RA, 14.5 months, range (1-68)] and 104 did not. Entry into the cohort was based on the absence of clinical arthritis at baseline but a positive ACPA and/or IgM-RF status and a history of arthralgia. 14-3-3η positivity was defined by the diagnostic cut-off of ≥0.19 ng/ml and a second cut-off of ≥0.80 ng/ml was set at the 75th percentile serum level of the group that did not develop RA. Fisher exact test and stepwise multivariate analyses were performed to determine 14-3-3η's association with other clinical/serological markers for RA development risk. Variables included in the model were ACPA positivity, alcohol non-use, VAS pain, morning stiffness and number of total painful joints.
Results 14-3-3η median plasma levels were significantly higher in the group that developed RA [0.9 (0.2-6.9) vs 0.3 (0.2-0.8) ng/ml, p<0.004]. ACPA levels were also differentially expressed (407 vs 54 IU/ml, p<0.001). Age, gender and RF titres did not differ between the groups. The Fisher exact test revealed that 14-3-3η levels at ≥0.19 ng/ml were associated with RA development with a likelihood ratio (LR) of 5.7 (p=0.02), a relative risk (RR) of 2.2 (95%CI: 1.0-4.5) and more significantly so at ≥0.80 ng/ml with an LR of 9.3 (p=0.002) and a RR of 2.2 (95%CI, 1.3-3.5). Alcohol non-use 1.7 (95%CI: 1.1-2.8), p=0.02 and ACPA positivity 7.9 (95%CI: 2.6-24.1), p<0.0001 but not RF, were also associated with RA development. In a multivariate analysis including these variables, 14-3-3η expression independently predicted RA development with a LR of 4.0 (p=0.05) at the ≥0.19ng/ml cut-off and more strongly so at the higher ≥0.80 ng/ml cut-off with a LR=5.9 (p=0.02).
Conclusions Plasma 14-3-3η titres are independently associated with RA development and levels ≥0.80 ng/ml are associated with a higher likelihood of developing RA. These findings are consistent with the mechanistic understanding of 14-3-3η's deleterious role in the pathophysiology of RA.
Disclosure of Interest D. van Schaardenburg: None declared, W. Maksymowych Consultant for: Augurex Life Sciences Corp, M. Boers: None declared, M. van Beers-Tas: None declared, A. Marotta Employee of: Augurex Life Sciences Corp