Background/Purpose: Serum 14-3-3η is an RA diagnostic marker
that is associated with radiographic progression risk. In vitro studies
describe 14-3-3η’s potent, dose-dependent up-regulation of factors that
perpetuate inflammation and joint damage. In this study we investigated the
association of 14-3-3η cut-points with standard RA disease activity
measures at a treatment-change clinical juncture.

Methods: Serum 14-3-3η levels were measured in 149 Japanese RA patients
prior to the initiation of therapy (BL) and at Yr1.
14-3-3η positivity was defined at 3 cut-points: the diagnostic
cut-off of ≥0.19 ng/ml, and 2x and 4x this cut-off, 0.40 and 0.80 ng/ml
respectively. Contingency analysis provided the relationship between
14-3-3η positivity and DAS, CDAI and SDAI categorization. Patients were
grouped into 4 categories based on the Yr1 14-3-3η positivity (≥0.19
ng/ml): remaining negative (RN), becoming positive (BP), remaining positive
(RP) or becoming negative (BN). Non-parametric ANOVA analysis and the Mann
Whitney U-test were utilized to assess group differences in disease activity
measures. The Fisher Exact Test was used to assess 14-3-3η’s association
with Good EULAR response.

Results: The mean (SD) age was 57 (15) years and 86% of the patients
were female. The median (IQR) disease duration was 51 (9-150) months. At the
diagnostic cut-point of ≥0.19 ng/ml, 14-3-3η positive patients had
worse disease based on significantly higher median DAS28ESR [5.62 (4.64-6.57)
vs. 4.77 (4.10-5.86), p=0.010], CDAI [24.7 (16.2-36.3) vs 16.0 (11.5-27.0),
p=0.015], and SDAI [26.8 (16.7-38.6) vs 18.8 (11.7-32.7), p=0.024]. Titres of
14-3-3η correlated significantly with DAS28ESR [r=0.29], CDAI [r=0.25],
SDAI [r=0.24], TJC28 [r=0.21], SJC28 [r=0.26] and JSN [r=0.18]. As shown in
Table 1, a stronger and more significant association with DAS28, CDAI and SDAI
categorization was observed at higher 14-3-3η positivity cut-offs.

Table 1. Baseline 14-3-3η positivity and association with Disease
State.

The match pairs t-test revealed that the 14-3-3η serum concentrations
significantly decreased from 0.70 ng/ml [0.17-5.96] at BL to 0.37 ng/ml
[0.11-1.82] at Yr1 (p<0.0001). At BL and Yr1, 110 (74%) and 97 (65%) were
14-3-3η +ve. At Yr 1, 18 of the 110 patients that were BL +ve were BN and
92 RP. In the BL-ve group, 5 patients sero-converted (BP) and 34 were RN at
Yr1. ANOVA and the U-test revealed that median Yr1 DAS28ESR was significantly
lower in the 18 BN patients compared to the 92 RP patients [2.0 (1.6-2.8) vs
2.7 (2.0-3.8), p=0.004]. The unpaired t-test, assuming equal variances,
revealed that mean DAS28ESR Yr1 levels were significantly lower in the 18 BN
patients compared to 5 BP patients [2.1 vs 3.1, p=0.033].

Conclusion: Serum 14-3-3η is a mechanistic marker that is
involved in the pathogenesis of RA. Patients who present with higher
14-3-3η titres reflect a higher disease status and may be considered for a
post-treatment measurement of 14-3-3η toward negative levels.