Background The 14-3-3 proteins are ubiquitously-expressed intracellular chaperonins. Expression of the η (eta) isoform is restricted to synovial and CNS tissues.¹ Extracellular 14-3-3η induces proinflammatory MAPK and NFkB cascades in THP-1 cells in vitro.² Extracellular 14-3-3η has been proposed as a novel biomarker for joint damage in rheumatoid arthritis (RA) and psoriatic arthritis, with serum elevation occurring in early RA. 14-3-3η positivity may add diagnostic sensitivity to laboratory RA markers such as rheumatoid factor (RF) and citrullinated cyclic peptide antibody (CCP).³ However, 14-3-3η expression in arthritogenic viral infection has not been studied.

Objectives The aim of this study was to determine the frequency of elevated 14-3-3η in patients with RA and in those with HCV, acute EBV, or acute B19 infections.

Methods We have developed a quantitative 14-3-3η sandwich ELISA and verified the reference range using 134 serum specimens from healthy donors (67 males, 67 females; ages 18-65). 14-3-3η was measured in de-identified residual clinical specimens originally submitted for routine RA or infectious disease diagnostic testing.

Results The 14-3-3η 95th-percentile reference range was defined as <0.2 ng/ml and the reportable range was <0.2 to >20.0 ng/mL. Six healthy subjects (4%) had elevated 14-3-3η levels; 2 of them were weakly RF positive. RF+/CCP+ subjects had the highest frequency of elevated 14-3-3η (56%) and the highest 14-3-3η median level (Table). Frequency of elevated 14-3-3η was lower in the RF+/CCP- and virus-infected groups and was comparable among the groups. None of the RF-/CCP+ subjects had elevated 14-3-3η, but the number of subjects was small (n=10). Frequency of elevated 14-3-3η in the RF-/CCP- group was 5%. Of 23 subjects with elevated 14-3-3η in the HCV group, 1 was RF+/CCP+, 13 RF+/CCP-, and 9 RF-/CCP-. Of 6 subjects with elevated 14-3-3η in the EBV group, 1 was RF+/CCP+, 2 RF+/CCP-, and 3 RF-/CCP+. All 5 subjects with elevated 14-3-3η in the B19 group were RF-/CCP-.

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Conclusions 14-3-3η elevation was most frequent among patients with RF+/CCP+ results (consistent with an RA diagnosis). 14-3-3η elevation also occurred less frequently in the RF+/CCP-, RF-/CCP-, HCV, EBV, and B19 groups. The data suggest that RA and some HCV, EBV, and parvovirus B19 infections may share pathogenetic mechanisms characterized by synovial release of 14-3-3η. Of note, the median abnormal 14-3-3η level was higher in the RF+/CCP+ group than in the virus-infected groups, suggesting less synovitis in viral arthritis than in RA, which is consistent with clinical observations.

References

1. Kilani et al. J Rheum 34:1650-7, 2007.

2. Marotta A. Arth Rheum 63 suppl 10: 1836, 2011

3. Maksymowych et al. Arth Rheum 64 suppl 10:977, 2012.

Disclosure of Interest O. Zhukov Employee of: Quest Diagnostics Nichols Institute, R. Abolhosn Employee of: Quest Diagnostics Nichols Institute, J. Popov Employee of: Quest Diagnostics Nichols Institute, S. Naides: None Declared