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FRI0226 93% of Early RA Patients Are Positive for 14-3-3Eta Markers and 14-3-3Eta Auto-Antibodies Inform A Favourable Prognosis, Irrespective of RF or ACPA Status
  1. D. van Schaardenburg1,
  2. M. Murphy2,
  3. S. Turk3,
  4. V.P. Bykerk4,
  5. E.C. Keystone5,
  6. K.A. Siminovitch5,
  7. A. Marotta6,
  8. W.P. Maksymowych7
  1. 1Reade, Amsterdam, Netherlands
  2. 2Augurex, Vancouver
  3. 3Reade, Netherlands, Canada
  4. 4Hosp Spec Surg, New York, United States
  5. 5Mt Sinai Hosp, Toronto
  6. 6Augurex, North Vancouver
  7. 7U of Alberta, Edmonton, Canada

Abstract

Background Particular emphasis has been placed on early identification of RA patients and joint damage risk stratification to improve patient outcomes. The 14-3-3η (eta) protein has been described as a mechanistic marker that is detectable in serum during the very early stages of RA development. 14-3-3η's extracellular expression in RA elicits a specific autoantibody (AAb) response that can be measured, and is postulated to be protective when it effectively clears systemic 14-3-3η.

Objectives This study examined the combined diagnostic strength of the 14-3-3η protein and its AAbs in early RA and whether the AAbs mark a favorable prognosis.

Methods 704 subjects were evaluated; 409 DMARD-naïve early RA patients from READE and 295 controls. Median age, disease duration, % females was 56 yrs, 4 mo, 73% with 69% and 63% being +ve for RF and ACPA. Controls included 106 healthy and 189 with either: connective tissue disease, OA, AS or autoimmune disorders. 14-3-3η protein levels were previously tested in this cohort using the 14-3-3η ELISA (+ve cut-off ≥0.19 ng/ml) and 67% of early RA patients were +ve. 14-3-3η AAb levels were measured on the MSD ECL platform. A diagnostic cut-off was determined by ROC curve analysis. The group that was 14-3-3η AAb-only +ve, in whom the 14-3-3η protein would have been cleared, was compared to the remainder of the cohort in terms of differences in radiographic progression over 3 yrs using the Mann-Whitney U-test. Fisher Exact test was used to determine the association between marker positivity and radiographic progression (SHS≥3 at yr 3).

Results Median (IQR) 14-3-3η AAb values were significantly higher in early RA [527U/ml (154-11762) vs all controls 264U/ml (96-1421), p<0.0001 delivering a ROC AUC of 0.85 (95%CI:0.82-0.88). When compared to healthy subjects, the ROC AUC was 0.92 (95%CI:0.89-0.95), p<0.0001 with the best cut-off of ≥380 U/ml delivering 93% specificity and 77% sensitivity with a likelihood ratio (LR) of 11.6. At this cut-off, 313 (77%) were 14-3-3η AAb +ve. Notably, 93% of early RA patients were +ve for either of the 14-3-3η markers and a Pearson correlation of r=-0.02 highlighted their complementary nature. Of the 409 patients, 105 (26%) were only +ve for the 14-3-3η AAbs and had significantly less joint damage progression at year 3, median (IQR) ΔSHS 0 (0-31) vs the rest of the cohort, 2 (-1–71), p<0.04. The Fisher exact test revealed that 14-3-3η AAb positivity (in the absence of the 14-3-3η protein) is associated with less radiographic progression at Year 3, LR=3.7 (p=0.04). Importantly, of the 105 AAb +ve patients, 37 (35%), 36 (34%) and 46 (44%) were +ve for ACPA, RF and ACPA/RF. Regression analysis in this group revealed that none of ACPA (p=0.3), RF (p=0.1) or the combination of RF/ACPA (p=0.2) were predictive of radiographic outcomes.

Conclusions 14-3-3η biomarkers identify 93% of early RA patients. Those who are uniquely positive for 14-3-3η AAbs have a favorable radiographic prognosis irrespective of ACPA or RF status. This is likely due to 14-3-3η AAbs' protective nature and effective clearance of deleterious 14-3-3η protein.

Disclosure of Interest D. van Schaardenburg: None declared, M. Murphy Employee of: Augurex Life Sciences Corp, S. Turk: None declared, V. Bykerk: None declared, E. Keystone: None declared, K. Siminovitch: None declared, A. Marotta Employee of: Augurex Life Sciences Corp, W. Maksymowych Consultant for: Augurex Life Sciences Corp

DOI 10.1136/annrheumdis-2014-eular.3323

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