14-3-3eta

Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) are the most commonly ordered laboratory tests to help diagnose rheumatoid arthritis. However, they may not be detectable in up to 50% of patients at the time of presentation and may remain negative in approximately 20% of patients. 

The 14-3-3 proteins are a family of seven isoforms that act as intracellular chaperones. 14-3-3eta is a proinflammatory protein that is produced by synovial cells in response to inflammation. It promotes the degradation of cartilage and stimulates osteoclasts to erode bone. Elevated serum levels are suggestive of inflammatory joint disease. This isoform is distinct from the 14-3-3 protein used to diagnose Creutzfeldt-Jakob disease.

Serum 14-3-3eta is an adjunctive test for rheumatoid arthritis that can be ordered in addition to RF and anti-CCP. The original study, using a cutoff of 0.19 ng/mL, determined a sensitivity of 63 to 77% and specificity of 93% in patients with established rheumatoid arthritis. Sensitivity decreased to 64% in patients with early disease. 

The main reason for ordering 14-3-3eta is to increase the likelihood of diagnosing seronegative rheumatoid arthritis. Elevated levels have been associated with more erosive disease. Serial measurements of serum 14-3-3eta may be helpful in determining therapeutic response. 14-3-3 has not been included in the ACR/EULAR classification for rheumatoid arthritis. 

14-3-3eta is measured by enzyme-linked immunosorbent assay. Specimen requirement is a red-top tube of blood.

Reference range is less than 0.19 ng/mL.

References

Maksymowych WP, et al. Serum 14-3-3η is a novel marker that complements current serological measurements to enhance detection of patients with rheumatoid arthritis. J Rheumatol. 2014 Nov; 41(11):2014-2013

Shovman O, Gilburd B, Watad A, Amital H, Langevitz P, Bragazzi NL, et al. The diagnostic value of 14-3-3η protein levels in patients with rheumatoid arthritis. Best Pract Res Clin Rheumatol 2018;32:610-7.

Subedi R, et al, Evaluation of 14-3-3eta protein as a diagnostic biomarker in the initial assessment of inflammatory arthritis, J Rheum Dis 2025;32(2):130-135.

Abdelhafiz D, Kilborn S, Bukhari M. The role of 14-3-3 η as a biomarker in rheumatoid arthritis. Rheumatol Immunol Res 2021;2:87-90.