Article Text

PDF
AB0152 14-3-3Eta Biomarker Dynamics in CIA Mark Disease Severity in A Non-Interventional Study
  1. A. Abulrob1,
  2. W.P. Maksymowych2,
  3. A. Marotta3
  1. 1National Research Council, Ottawa
  2. 2U of Alberta, Edmonton
  3. 3Augurex, Vancouver, Canada

Abstract

Background Biomarkers are increasingly used in RA interventional studies as indicators of efficacy/safety/prognosis. We previously reported that serum 14-3-3η (eta) and its auto-antibodies (AAbs) are mechanistic markers that inform RA therapy response. 14-3-3η has been identified as a drug target because it potently induces inflammatory and joint damage factors. Prospective clinical studies demonstrate that 14-3-3η may predispose to, and its AAbs may protect from radiographic progression. Such non-interventional biomarker dynamics may strategically guide therapeutic development programs.

Objectives To examine serum dynamics of 14-3-3η markers along the arthritis disease course in a non-interventional study using a collagen-induced arthritis (CIA) murine model.

Methods Thirteen DBA/1LacJ mice were induced with 100μl of RA agent; 0.1mg of collagen+0.1mg of M. tuberculosis administered once, intradermally at the base of the tail for a 52-day disease course. Serum was collected on induction, sacrifice day and every 3 days in between. Animals were sacrificed either due to study conclusion (Day 52) or severity of arthritis symptoms measured by visual arthritis score (0-4) and left/right paw caliper measurements (mm2). Mice were divided into 2 severity groups, 'severe' defined by early sacrifice Days 35/38 (N=5) or 'mild' by late sacrifice, Day 45/52 (N=8). 2-tailed paired t-tests were used to compare mean differences in biomarker expression between induction and sacrifice days. A Pearson correlation was run between 14-3-3η protein and AAbs in the two severity groups. Due to 14-3-3η protein and AAb expression range disparity, [protein/(Log10 AAbs)] x 100 was used to reach a biomarker unit ratio. For survival analysis, the groups were defined by above or below the mean 14-3-3η ratios of the induction and sacrifice date. A Kaplan-Meier curve was generated, the Log-Rank Mantel-Cox test was used for curve comparisons and a Hazard ratio determined.

Results At induction, 14-3-3η mean (SD) serum levels were similar in the severe and mild arthritis groups, 0.21 (0.11) and 0.28 (0.10)ng/ml, p=0.26, and decreased significantly by sacrifice date in the mild group to 0.04 (0.03)ng/ml, p=0.00008 but not in the severe 0.14 (0.14)ng/ml p=0.27. Both had a significant increase in 14-3-3η AAb titres (U/ml) by the sacrifice date; 53 to 364, p=0.01 and 28 to 278, p=0.001. The 14-3-3η protein:AAb ratios by paired t-test were significantly lower at sacrifice vs. induction date in the mild group (1.8 vs. 19.4 p=0.00008) while the change was not significant in the severe group (5.5 vs. 14.3, p=0.07). 14-3-3η AAb levels in the mild group correlated inversely and strongly with 14-3-3η protein levels (r=-0.84, p=0.002), but not in the severe (p=0.75). The survival groups were defined as mice achieving a protein:AAb ratio reduction of >10 (N=8) or <10 (N=5) by sacrifice date. The group that had >10 ratio reduction (and therefore lower protein burden) had longer median survival of 45 versus 36 days (95%CI:0.47-1.1). The Mantel-Cox test returned a Chi-sq of 6.6 p=0.01 and the Hazard ratio was 9.6 (95%CI:1.7-54.0).

Figure

Conclusions Consistent with 14-3-3η expression in RA, higher serum levels are deleterious in CIA and clearance of the protein by 14-3-3η AAbs results in less severe arthritis and longer survival. 14-3-3η may assist with drug development programs and should be tested further for personalized medicine strategies.

Disclosure of Interest A. Abulrob: None declared, W. Maksymowych Consultant for: Augurex Life Sciences Corp, A. Marotta Employee of: Augurex Life Sciences Corp

DOI 10.1136/annrheumdis-2014-eular.3427

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.