For the past several years, I've followed the research about the test for 14-3-3? (or 14-3-3eta) and talked about it with patients on Facebook and on my blog. Let’s take a closer look at how the test can be used in RA and why it’s so valuable. The 14-3-3? protein’s role in RA was first recognized in 2007. As part of a family of regulatory proteins the “eta” family member was present at a significantly higher level in the synovial fluid and serum of people with RA compared to those without.
Since then, a simple blood test to detect 14-3-3? has become available.
Interestingly, in both early and established RA, 14-3-3? levels did not necessarily correlate with tests often used to judge rheumatoid disease activity levels (DAS28 scores or CRP levels). So, it is a unique test that measures a protein that other tests don’t.
Studies showed that the protein levels are actually linked with the processes of joint damage and progression of rheumatoid disease. It stimulates inflammatory factors in RA (like IL-1 and IL-6). And it has been shown to be related to the development of the arthritis itself, often present before diagnosis.
Let’s look at three ways that the test can be used to help people with rheumatoid disease.
1. It can contribute to earlier RA diagnosis
Studies show that 14-3-3? is present during what some call the “pre-clinical” phase of RA. During this time, people may notice pain or other changes, but they do not necessarily meet the clinical criteria for diagnosis. Of course early diagnosis and treatment can lead to a better treatment response and even prevent the damage of advanced disease.
LabCorp and Quest Diagnostics include this protein in its RA diagnostic panels (RheumAssure™ and IdentRA®) because it may improve diagnostic sensitivity and they also note the role it plays in joint erosion. “Concentrations are significantly higher in people with active joint disease than in those with inactive RA or psoriasis without arthritis.”
2. It can help show a medicine is working
Here are some of the medicines that have already been studied:
Tofacitinib (Xeljanz): Levels of 14-3-3? are significantly lower after a person is treated with tofacitinib. And people taking tofacitinib who show improvement with several different types of disease activity scores also have lower levels of 14-3-3?.
Tocilizumab (Actemra): The 14-3-3? test is very useful for identifying patients with high disease activity. And its levels have been shown to change when patients respond to tocilizumab. Patients whose levels became negative after one year of tocilizumab treatment were more likely to be in remission—even though patients with positive 14-3-3? had more severe disease before treatment.
Upadacitinib (Rinvoq): Changes in 14-3-3? levels also correlate with improvement for patients taking upadacitinib according to several disease activity measures. As treatment with upadacitinib improves disease activity, the levels of this marker also significantly reduce.
3. It can detect joint damage during “clinical remission”
Clinical diagnosis of RA and joint counts to measure disease activity both rely on obvious joint swelling and objective indicators of inflammation (usually CRP). However, the same way PRD already experience RA symptoms in the “pre-clinical” time before diagnosis, they can also experience disease damage during apparent “remission.” But the 14-3-3? test can show whether the disease is really active.
A Canadian study found that PRD with higher test levels were more likely to experience joint damage and less likely to ever reach “SDAI remission.” Additionally, those with higher scores who did reach remission were more likely to continue to experience joint damage.
A Japanese trial looked at what happens when adalimumab (Humira) is discontinued for PRD who are in clinical remission. They found that PRD with a high level of 14-3-3? were more likely to flare (even if they had a low CRP). This shows that the joint damage process is separate from the idea of “inflammation.”
A test that supports early and aggressive RA treatment
The 14-3-3? test is used to help detect RA and erosive psoriatic arthritis. It also signals whether someone’s disease is more destructive. It is so important to use every tool available for RA testing because it is still early in understanding all of the processes of the disease and its effects. Doctors and patients will need to learn how to optimize strategies to better treat the damage, pain, and disability of RD.
Where to get a 14-3-3? test for yourself or a family member:
14-3-3?: a protein associated with damage and disease progression in RA
CRP: c-reactive protein is made by the liver often as a response to inflammation
DAS28: a type of disease activity score in RA that includes 28 joints
PRD: people with rheumatoid disease
RA / RD: rheumatoid arthritis / rheumatoid disease
SDAI: simple disease activity index that includes 28 joints and global assessments of disease and CRP
Synovial: tissue around joints
Maksymowych WP, van der Heijde D, Allaart CF, Landewé R, Boire G, Tak PP, Gui Y, Ghahary A, Kilani R, Marotta A. 14-3-3? is a novel mediator associated with the pathogenesis of rheumatoid arthritis and joint damage. Arthritis Res Their 2014;16, R99. Available from https://doi.org/10.1186/ar4547
van Beers-Tas MH, Marotta A, Boers, Maksymowych MWP, van Schaardenburg D. A prospective cohort study of 14-3-3? in ACPA and/or RF-positive patients with arthralgia. Arthritis Res Their 2016;18,76. Available from: https://doi.org/10.1186/s13075-016-0975-4
Shovman O , Gilburd B , Watad A , Amital H, Langevitz P, Bragazzi NL , Adawi M, Perez D , Lidar M, Katz I , Blank M , Biln NK , Marotta A, Shoenfeld Y. Decrease in 14-3-3? protein levels is correlated with improvement in disease activity in patients with rheumatoid arthritis treated with Tofacitinib. Pharmacol Res 2019;141:623-626. Available from: https://doi.org/10.1016/j.phrs.2018.11.009
Hirata S, Marotta A, Gui Y, Hanami K, Tanaka Y. Serum 14-3-3? level is associated with severity and clinical outcomes of rheumatoid arthritis, and its pretreatment level is predictive of DAS28 remission with tocilizumab. Arthritis Res Their 2015;17: 280. Available from: https://doi.org/10.1186/s13075-015-0799-7
Sornasse T, Chahal S, Gui Y, Nagarajan N, Friedman A, Biln N. Correlation of Plasma 14-3-3? Levels with Disease Activity Measures in Methotrexate Naïve RA Patients Treated With Upadacitinib Monotherapy in the Select-Early Phase 3 Study. Ann Rheum Dis 2020;79:1351. Available from: https://ard.bmj.com/content/79/Suppl_1/1351.2
Carrier N, Marotta A, de Brum-Fernandes, AJ, Liang P, Masetto A, Ménard HA, Maksymowych WP, Boire G. Serum levels of 14-3-3? 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 Their 2016;18, 37. Available from: https://doi.org/10.1186/s13075-016-0935-z
Hirata S, Marotta A, Hanami K, Tanaka Y. 14-3-3eta Predicts Joint Damage Progression and Flaring after Adalimumab Discontinuation. Ann Rheum Dis 2017;76:791 (abstract SAT0061). Available from: https://ard.bmj.com/content/annrheumdis/76/Suppl_2/791.3.full.pdf