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.
« Back to 2014 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/14-3-3%ce%b7-citarg-antibody-ratios-are-we-overlooking-the-prognostic-utility-of-citrullinated-antibodies-by-only-looking-at-titers/