patient care perspectives

Use of 14-3-3η Protein, Multi-Biomarker Disease Activity, and Other Emerging Tests to Profile Patients With Rheumatoid Arthritis

by Jonathan Kay, MD


In certain clinical scenarios, new diagnostic tests such as 14-3-3η protein and multi-biomarker disease activity (MBDA) have been shown to offer additive value in the diagnosis and prognosis of patients with rheumatoid arthritis (RA). Such molecular profiling may have useful applications, including in the identification of patients who require less intensive therapy.

Expert Commentary

Jonathan Kay, MD

Professor of Medicine and Population and Quantitative Health Sciences
Timothy S. and Elaine L. Peterson Chair in Rheumatology
Director of Clinical Research, Rheumatology
University of Massachusetts Medical School
Worcester, MA

“The MBDA score predicts structural progression and might be used to determine which patients may not need more aggressive therapy.” 

Jonathan Kay, MD

14-3-3η is a specific isoform of a family of intracellular proteins that are expressed exclusively in eukaryotic cells. These proteins bind to and regulate the biologic activity of more than 200 intracellular proteins and are involved in regulating protein trafficking, cellular signaling, and cytoskeletal transport. 14-3-3η is overexpressed in patients with RA compared with healthy patients and those with osteoarthritis, axial spondyloarthritis, or gout. It induces proinflammatory cytokines, RANKL, and matrix metalloproteinases, which are involved in joint damage, and thus it may predict radiographic progression in patients with early and established RA. 14-3-3η is a biomarker that has been detected in patients who are otherwise seronegative by lacking rheumatoid factor or anti–citrullinated protein antibodies. Further, it may be complementary to these other biomarkers in the diagnosis of RA (eg, the presence of 14-3-3η in addition to rheumatoid factor and/or anti–citrullinated protein antibodies incrementally increases the likelihood of an RA diagnosis). Patients with low baseline levels of 14-3-3η (<0.5 ng/mL) appear to have a lower risk of radiographic progression and may not need medical treatment that is as aggressive as those with higher levels. However, prospective studies are needed to confirm the utility of 14-3-3η as a predictive biomarker.

The MBDA test Vectra DA measures concentrations of 12 biomarkers to generate a score that ranges from 0 to 100. Based on the MBDA score, disease activity categories of remission, low, moderate, and high disease activity have been established. The MBDA score may provide additional utility in assessing RA disease activity to that of individual acute phase reactants, such as the sedimentation rate and C-reactive protein (CRP). Data indicate that the sedimentation rate and CRP are both within the normal range in more than half of patients with active RA, as defined by a Clinical Disease Activity Index score higher than 2.8 (indicating at least low disease activity). Thus, there is a need for a laboratory test that measures more than a single acute phase reactant to assess RA disease activity.

Data from the SWEFOT trial have demonstrated that the baseline MBDA score is a strong predictor of radiographic progression. Among patients with RA with high disease activity (MBDA score >44) despite methotrexate monotherapy, 20.9% exhibited radiographic progression at 1 year compared with 3.4% of those with moderate disease activity (MBDA score 30-44) and none of those with low disease activity (MBDA score <30). These findings indicate that the MBDA score predicts structural progression and might be used to determine which patients may not need more aggressive therapy.


Barber CEH, Zell J, Yazdany J, et al. 2019 American College of Rheumatology recommended patient-reported functional status assessment measures in rheumatoid arthritis. Arthritis Care Res (Hoboken). 2019 Nov 11. doi: 10.1002/acr.24040. [Epub ahead of print]

Calabrese LH. MBDA: a valuable tool for medical decision making. J Rheumatol. 2019;46(12):1642.

Carrier N, Marotta A, de Brum-Fernandes AJ, et al. 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. 2016;18:37.

England BR, Tiong BK, Bergman MJ, et al. 2019 update of the American College of Rheumatology recommended rheumatoid arthritis disease activity measures. Arthritis Care Res (Hoboken). 2019 Nov 11. doi: 10.1002/acr.24042. [Epub ahead of print]

Hambardzumyan K, Bolce R, Saevarsdottir S, et al. Pretreatment multi-biomarker disease activity score and radiographic progression in early RA: results from the SWEFOT trial. Ann Rheum Dis. 2015;74(6):1102-1109.

Hambardzumyan K, Bolce RJ, Wallman JK, van Vollenhoven RF, Saevarsdottir S. Serum biomarkers for prediction of response to methotrexate monotherapy in early rheumatoid arthritis: results from the SWEFOT trial. J Rheumatol. 2019;46(6):555-563.

Maiijer KI, Wanying L, Sasso EH, et al. Does the multi-biomarker disease activity score have diagnostic value in early rheumatoid arthritis and unclassified arthritis? Ann Rheum Dis. 2015;74(11):2097-2099.

Maksymowych WP, van der Heijde D, Allaart CF, et al. 14-3-3η is a novel mediator associated with the pathogenesis of rheumatoid arthritis and joint damage. Arthritis Res Ther. 2014;16(2):R99.

Nowell WB, Curtis JR, Nolot SK, et al. Digital tracking of rheumatoid arthritis longitudinally (digital) using biosensor and patient-reported outcome data: protocol for a real-world study. JMIR Res Protoc. 2019;8(9):e14665.

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