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Abstract Number: 359

14-3-3η Cit:Arg Antibody Ratios:  Are We Overlooking the Prognostic Utility of Citrullinated Antibodies By Only Looking at Titers?

Anthony Marotta1, Samina Turk2, Mairead Murphy3, Walter P. Maksymowych4 and Dirkjan van Schaardenburg5, 11423 Dempsey Road, Augurex Life Sciences Corp., North Vancouver, BC, Canada, 2Reade, Amsterdam, Netherlands, 3Augurex Life Sciences Corp., North Vancouver, BC, Canada, 4Department of Medicine, University of Alberta, Edmonton, AB, Canada, 5Dr Jan van Breemenstraat 2, Reade, Amsterdam, Netherlands

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: autoantibodies, citrullination, Prognostic factors and rheumatoid arthritis (RA)

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Session Information

Session Title: Rheumatoid Arthritis - Clinical Aspects: Novel Biomarkers and Other Measurements of Disease Activity

Session Type: Abstract Submissions (ACR)

Background/Purpose Citrullination is a post-translational modification whereby arginine (Arg) is deiminated by PAD enzymes to form citrulline (Cit). In RA, there are auto-antibodies (AAb) to Cit and native proteins1, 2. With other types of PTM, such as phosphorylation, modifications are assessed as a degree of change in reactivity from the native state to inform biochemically relevant and potentially deleterious events. Current ACPA assays are designed to measure reactivity to the Cit form of a peptide without accounting for the relative change in Cit:Arg reactivity. This may overlook important information related to citrullination and its relationship with clinical outcomes. 14-3-3η is a ubiquitous intracellular protein whose extracellular expression in RA leads to its citrullination and the development of specific cit-reactive AAb. In this study we investigated whether anti-cit 14-3-3η AAbs inform joint damage prognosis in early RA.

Methods Anti-cit 14-3-3η levels were measured in 139 DMARD-naïve early RA patients from the READE cohort using the MSD ECL platform, 4 highly reactive 14-3-3η cit/arg peptides formed the basis of the assay. For each of the 4 sites, citrullination reactivity was defined as a 50% increase in Cit:Arg read units. Overall anti-cit-14-3-3η positivity was defined as reactivity to at least one of the four sites. Contingency analysis was used to assess the association between ACPA and 14-3-3η anti-cit:arg ratio positivity. Univariate and stepwise multivariate analyses were performed to identify predictors of radiographic damage progression (DSHS year 3 ≥ 3.0).

Results Of 139 patients, 71% were ACPA positive and 51% were 14-3-3η anti-cit:arg ratio positive. A univariate analysis evaluating the association of anti-cit-14-3-3η titres and cit:arg ratios with radiographic progression revealed that the ratios were significantly associated (p<0.01) while titres were not. Contingency analysis revealed a strong association between APCA and 14-3-3η anti-cit:arg ratios, LR=19.1 p<0.0001. By Fisher Exact test, ACPA and 14-3-3η anti-cit:arg ratios were associated with radiographic progression at yr 3; LR=5.3 p=0.02 and 6.4 p=0.01, respectively. In a model incorporating ACPA and 14-3-3η anti-cit:arg ratio controlling for baseline total sharp score, the ratios independently predicted radiographic progression Chi-Sq=6.4 p=0.01, while ACPA did not. In a multivariate model including baseline TSS, disease duration, age, ESR, gender together with RF, 14-3-3η and 14-3-3η anti-cit:arg ratio positivity, the only independent predictors of radiographic damage progression were 14-3-3η protein and the cit:arg ratios; Chi-Sq=5.2 (p=0.02) and 4.0 (p=0.05), respectively.

Conclusion Both the 14-3-3η protein and 14-3-3η anti-cit:arg ratios are independent predictors of radiographic progression. The ratios (but not anti-cit-14-3-3η titres) are a stronger predictor than ACPA. These data underscore 1) the potential benefit of accounting for cit:arg ratios rather than only cit titres in cit assays and 2) that the prognostic utility of 14-3-3η anti-cit:arg ratios should be further investigated.

1. Brink et al. ARD 73.7 (2014): e46.

2. van de Stadt et al. ARD 70.1 (2011): 128.


Disclosure:

A. Marotta,

Augurex Life Sciences Corp.,

3;

S. Turk,
None;

M. Murphy,

Augurex Life Sciences Corp,

3;

W. P. Maksymowych,

Augurex Life Sciences Corp,

5;

D. van Schaardenburg,

Augurex Life Sciences Corp,

5.

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