Background Extracellular 14-3-3eta (η) is a soluble ligand that potently induces matrix metalloproteinases, in a dose-dependent manner. This, taken together with 14-3-3η's reported diagnostic utility, underscores the prognostic potential of this mechanistic biomarker.
Objectives This study sought to examine 14-3-3η's expression in early RA and whether various cut-offs inform a higher likelihood of radiographic changes over 3 years.
Methods Baseline serum 14-3-3η levels were measured in a cohort of 409 early RA patients; all patients were treatment naive at baseline. Median patient age was 56 years and 73% were female. Radiographic progression was defined as a ΔSHS ≥3 over 3 years. Three 14-3-3η concentration cut-offs were selected as follows: the reported manufacturer's (Augurex 14-3-3η ELISA) reference range ≥0.19 ng/ml and at the 50th and 75th percentile in the group that progressed, namely 0.40 and 3.0 ng/ml. Two-tailed Mann-Whitney U-tests were used to assess group differences. Fisher's exact test was utilized to examine 14-3-3η's association with radiographic outcomes. Log transformation was used to determine 14-3-3η, RF and ACPA titres association with radiographic changes. Stepwise multivariate regression analysis was performed incorporating disease duration, age, gender, TJC28, SJC28, ESR and CRP with 14-3-3η titres. Likelihood ratios (LR), odds ratios (OR) and corresponding confidence intervals (CI) are reported.
Results Of this early RA cohort, 275 (67%) were 14-3-3η positive, 259 (63%) were positive for RF and 282 (69%) for ACPA. Baseline 14-3-3η median (IQR) levels were higher in patients that progressed compared to those that did not [1.02ng/ml (0.18-6.40) vs. 0.44ng/ml (0.07-2.85), p=0.01]. Median RF titres were also higher in patients that progressed by year 3 [70 IU/ml (24-200) vs. 40IU/ml (10-117), p=0.003], but ACPA titres were not (p=0.12). Over the 3 years, RF or ACPA positive patients had significantly higher median ΔSHS than ACPA negatives, 2.0 vs. 0.0, p=0.001 and 2.0 vs. 0.0, p=0.002. Similarly, 14-3-3η positive patients (≥0.19) had significantly higher median ΔSHS than the negatives, 2.0 vs. 0.0, p=0.009, and significantly lower ΔDAS28 and ΔSJC28, 1.9 vs. 2.4, p=0.01 and 5.0 vs. 8.0, p=0.0002, respectively. The Fisher exact test revealed that 14-3-3η at ≥0.19, ≥0.40 and ≥3.0 ng/ml was associated with increasing LRs for radiographic progression at year 3; ≥0.19 ng/ml [LR=6.3 (p=0.009), OR=1.8 (95%CI 1.1-2.8)], ≥0.40ng/ml [LR=6.6 (p=0.007), OR=1.7 (95%CI 1.1-2.6)]and ≥3.0ng/ml [LR=8.8 (p=0.002) OR=1.9 (95%CI 1.3-3.0)]. Log transformation of the 3 serological variables revealed that only 14-3-3η titres were associated with radiographic outcomes yielding an LR of 6.0, p=0.01. In a multivariate model, independent predictors of ΔSHS ≥3 over 3 years were disease duration (LR=8.3, p=0.0041) and 14-3-3η titres (LR=6.2, p=0.013).
Conclusions 14-3-3η is an independent predictor of radiographic outcomes in early RA and higher levels inform a higher likelihood of joint damage progression over 3 years. These clinical observations align with 14-3-3η's mechanistic role as a potent, dose-dependent upregulator of the matrix metalloproteinases.
Disclosure of Interest : D. van Schaardenburg: None declared, W. Maksymowych Consultant for: Augurex Life Sciences Corp, M. Boers: None declared, S. Turk: None declared, A. Marotta Employee of: Augurex Life Sciences Corp