J Rheum Dis.  2025 Apr;32(2):130-135. 10.4078/jrd.2024.0110.

Evaluation of 14-3-3eta protein as a diagnostic biomarker in the initial assessment of inflammatory arthritis

Affiliations
  • 1Division of Rheumatology, MedStar Washington Hospital Center, Washington, DC, USA
  • 2Department of Medicine, Immunology & Rheumatology, Rochester Regional Health, Rochester, New York, USA
  • 3Division of Allergy, Immunology & Rheumatology, Rochester Regional Health, Rochester, New York, USA
  • 4Division of Rheumatology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA

Abstract


Objective
Serum 14-3-3eta are novel biomarkers of rheumatoid arthritis (RA). It is not clear whether 14-3-3eta may be present in other forms of inflammatory arthritis (IA). We evaluated the presence of 14-3-3eta as a diagnostic biomarker in the evaluation IA.
Methods
A retrospective cohort study of adult patients who were evaluated for IA by a rheumatologist with a result for the lab test of 14-3-3eta was conducted.
Results
Of 280 included patients, 30% were diagnosed with RA, 11% with psoriatic arthritis (PsA), and 59% with another condition. Twenty-four (9%) patients had positive results for 14-3-3eta. Fifty-two percent of positive patients were diagnosed with RA, with 48% having another diagnosis including axial spondyloarthritis, gout, Sjögren’s, undifferentiated IA, diabetic cheiroarthropathy, prostate cancer with bone metastasis, osteoarthritis, unspecified arthralgia. No patients with PsA had a positive value. RA patients had a higher value for 14-3-3eta compared to non-RA (5.44 [1.56~9.31] vs. 0.69 [0.40~0.98] ng/mL, p=0.03, square brackets are 95% confidence interval values). The mean value for the 14-3-3eta in seropositive RA trended higher than seronegative (8.0 [2.3~13.7] vs. 1.4 [0.4~2.4] ng/mL, p=0.06). In the RA cohort, elevated 14-3-3eta was associated with elevated erythrocyte sedimentation rate (odd ratio=6.62 [1.24~47.09], p<0.04), but not other variables.
Conclusion
14-3-3eta may aid as a diagnostic biomarker of RA. However, it is not specific for RA, especially at low positive levels, and may be positive in other forms of IA. Ideal cutoff values need to be established for RA and non-RA conditions. It was not found in PsA.

Keyword

14-3-3eta proteins; Biomarkers; Rheumatoid arthritis; Psoriatic arthritis; Inflammatory arthritis

Reference

1. Gavrilă BI, Ciofu C, Stoica V. 2016; Biomarkers in rheumatoid arthritis, what is new? J Med Life. 9:144–8.
2. Nishimura K, Sugiyama D, Kogata Y, Tsuji G, Nakazawa T, Kawano S, et al. 2007; Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med. 146:797–808. DOI: 10.7326/0003-4819-146-11-200706050-00008. PMID: 17548411.
3. Kay J, Upchurch KS. 2012; ACR/EULAR 2010 rheumatoid arthritis classification criteria. Rheumatology (Oxford). 51 Suppl 6:vi5–9. DOI: 10.1093/rheumatology/kes279. PMID: 23221588.
4. Carrier N, Marotta A, de Brum-Fernandes AJ, Liang P, Masetto A, Ménard HA, et al. 2016; Serum levels of 14-3-3η protein supplement C-reactive protein and rheumatoid arthritis-associated antibodies to predict clinical and radiographic outcomes in a prospective cohort of patients with recent-onset inflammatory polyarthritis. Arthritis Res Ther. 18:37. DOI: 10.1186/s13075-016-0935-z. PMID: 26832367. PMCID: PMC4736641.
5. Kilani RT, Maksymowych WP, Aitken A, Boire G, St-Pierre Y, Li Y, et al. 2007; Detection of high levels of 2 specific isoforms of 14-3-3 proteins in synovial fluid from patients with joint inflammation. J Rheumatol. 34:1650–7.
6. Wang D, Cui Y, Lei H, Cao D, Tang G, Huang H, et al. 2020; Diagnostic accuracy of 14-3-3 η protein in rheumatoid arthritis: a meta-analysis. Int J Rheum Dis. 23:1443–51. DOI: 10.1111/1756-185X.13921. PMID: 32909672. PMCID: PMC7756802.
7. Guan SZ, Yang YQ, Bai X, Wang Y, Feng KQ, Zhang HJ, et al. 2019; Serum 14-3-3η could improve the diagnostic rate of rheumatoid arthritis and correlates to disease activity. Ann Clin Lab Sci. 49:57–62.
8. Hirata S, Marotta A, Gui Y, Hanami K, Tanaka Y. 2015; Serum 14-3-3η level is associated with severity and clinical outcomes of rheumatoid arthritis, and its pretreatment level is predictive of DAS28 remission with tocilizumab. Arthritis Res Ther. 17:280. DOI: 10.1186/s13075-015-0799-7. PMID: 26449724. PMCID: PMC4599751.
9. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010; 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 62:2569–81. DOI: 10.1002/art.27584. PMID: 20872595.
10. Taylor W, Gladman D, Helliwell P, Marchesoni A, Mease P, Mielants H. CASPAR Study Group. 2006; Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum. 54:2665–73. DOI: 10.1002/art.21972. PMID: 16871531.
11. Aringer M, Costenbader K, Daikh D, Brinks R, Mosca M, Ramsey-Goldman R, et al. 2019; 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Arthritis Rheumatol. 71:1400–12.
12. Haugen IK, Felson DT, Abhishek A, Berenbaum F, Bierma-Zeinstra S, Dziedzic KS, et al. 2024; 2023 EULAR classification criteria for hand osteoarthritis. Ann Rheum Dis. 83:1428–35. DOI: 10.1136/ard-2023-225073. PMID: 38821712. PMCID: PMC11503154.
13. R Core Team. c2021. R: a language and environment for statistical computing [Internet]. R Foundation for Statistical Computing;Vienna: https://www.R-project.org/. cited 2024 Sep 20.
14. Shovman O, Gilburd B, Watad A, Amital H, Langevitz P, Bragazzi NL, et al. 2018; The diagnostic value of 14-3-3η protein levels in patients with rheumatoid arthritis. Best Pract Res Clin Rheumatol. 32:610–7. DOI: 10.1016/j.berh.2019.01.010. PMID: 31174829.
15. Yarlagadda LD, Jacob R, Rajasekhar DL, Iyyapu KM, Kompella SBSS, Madrol VB, et al. 2020; Evaluation of a new biomarker 14-3-3 eta protein in diagnosis of rheumatoid arthritis. Indian J Rheumatol. 15:175–80. DOI: 10.4103/injr.injr_30_20.
16. Marotta A, Kuijk A, Maksymowych W, Tak PP. 2013; SAT0309 Serum 14-3-3 ETA: an independent biomarker associated with joint damage in psoriatic arthritis. Ann Rheum Dis. 71(Suppl 3):576. DOI: 10.1136/annrheumdis-2012-eular.3256.
17. Dougherty MK, Morrison DK. 2004; Unlocking the code of 14-3-3. J Cell Sci. 117:1875–84. DOI: 10.1242/jcs.01171. PMID: 15090593.
18. Maksymowych WP, van der Heijde D, Allaart CF, Landewé R, Boire G, Tak PP, et al. 2014; 14-3-3η is a novel mediator associated with the pathogenesis of rheumatoid arthritis and joint damage. Arthritis Res Ther. 16:R99. DOI: 10.1186/ar4547. PMID: 24751211. PMCID: PMC4060379.
19. Ulijn E, den Broeder N, Ten Cate D, van Overdijk K, Demirel H, Landewé R, et al. 2024; Limited diagnostic and prognostic value of routine radiographs in newly presenting arthritis suspected of rheumatoid arthritis: a retrospective study. Arthritis Care Res (Hoboken). 76:497–502. DOI: 10.1002/acr.25271. PMID: 37933435.
20. Salman E, Çetiner S, Boral B, Kibar F, Erken E, Ersözlü ED, et al. 2019; Importance of 14-3-3eta, anti-CarP, and anti-Sa in the diagnosis of seronegative rheumatoid arthritis. Turk J Med Sci. 49:1498–502. DOI: 10.3906/sag-1812-137. PMID: 31651120. PMCID: PMC7018368.
21. Huang J, Zeng T, Zhang X, Tian Y, Wu Y, Yu J, et al. 2020; Clinical diagnostic significance of 14-3-3η protein, high-mobility group box-1, anti-cyclic citrullinated peptide antibodies, anti-mutated citrullinated vimentin antibodies and rheumatoid factor in rheumatoid arthritis. Br J Biomed Sci. 77:19–23. DOI: 10.1080/09674845.2019.1658425. PMID: 31433746.
22. Zeng T, Tan L, Wu Y, Yu J. 2020; 14-3-3η Protein in rheumatoid arthritis: promising diagnostic marker and independent risk factor for osteoporosis. Lab Med. 51:529–39. DOI: 10.1093/labmed/lmaa001. PMID: 32080735.
23. Abdelhafiz D, Kilborn S, Bukhari M. 2021; The role of 14-3-3 η as a biomarker in rheumatoid arthritis. Rheumatol Immunol Res. 2:87–90. DOI: 10.2478/rir-2021-0012. PMID: 36465971. PMCID: PMC9524784.
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