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THU0244 14-3-3Eta is an Independent Predictor of Radiographic Changes in Early RA and Higher Titres Inform A Higher Likelihood of Joint Damage Progression
  1. D. van Schaardenburg1,
  2. W.P. Maksymowych2,
  3. M. Boers3,
  4. S. Turk4,
  5. A. Marotta5
  1. 1Reade, Amsterdam, Netherlands
  2. 2University of Alberta, Edmonton, Canada
  3. 3VU University Medical Center
  4. 4Reade, Amsterdam, Netherlands
  5. 5Augurex, Vancouver, Canada

Abstract

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

DOI 10.1136/annrheumdis-2014-eular.3320

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