You enter the exam room and greet your patient, a 38-year-old mother of three, including a 1-year-old boy she has with her today. She’s asked to see you because she’s been experiencing pain and tenderness in her wrist joints for several months. She had rationalized the pain by attributing it to toting her baby around and “approaching 40,” but her husband urged her to have it checked out.
Your history and exam lead you to suspect rheumatoid arthritis (RA). The patient reported fatigue and loss of appetite, in addition to having a low-grade fever and bilateral wrist pain. Still, this patient’s symptoms could indicate other types of inflammatory arthritis, and her mother had osteoarthritis (OA), so you would like to do some further investigation before referring her to a rheumatologist. If it is RA, you want to make a diagnosis supported by lab testing as quickly as possible, before significant joint erosion occurs.
Unfortunately, diagnosing any autoimmune disease can be challenging—symptoms can overlap and vary from patient to patient. In most cases, there is no single test to help diagnose an autoimmune disease and diagnoses often require a combination of clinical factors and laboratory tests. In addition, most markers used to test specifically for RA are suboptimal:
- An antinuclear autoantibody (ANA) screen for autoimmune disease can test negative in a patient with early, subclinical RA
- C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are general inflammatory markers, but not specific to RA
- Rheumatoid factor (RF) has low sensitivity and low specificity
- Cyclic citrullinated peptide (CCP) has low sensitivity, but high specificity for RA; however, it is underutilized in primary care
- RF and CCP together demonstrate low sensitivity in early RA, not optimal for screening
- Many patients with RA are seronegative for RF and CCP
14-3-3η (eta): a diagnostic RA biomarker
Fortunately, there is a test that helps diagnose RA. The IdentRA® panel includes the markers RF and CCP, as well as 14-3-3η, a protein biomarker that helps diagnosis of early and established RA.1,2,3 14-3-3 proteins are molecular chaperones critical to the regulation of intracellular functions. 14-3-3η is released extracellularly in the surrounding synovial fluid and peripheral blood when there is joint inflammation. The “eta” isoform is often found in significantly higher amounts in the serum and synovial fluid of individuals with inflamed joints compared with those with inactive RA or psoriasis without arthritis.
An added advantage of 14-3-3η is that it is not just mechanistic, it is modifiable—its measurable level declines when the patient is responding to therapy. Together, these 2 characteristics make 14-3-3η clinically actionable across the RA patient care continuum:
RA screen. 14-3-3η is not usually elevated in OA and aids in differential diagnosis between RA and OA.4
RA prognosis. Decreased levels of 14-3-3η are associated with better clinical outcomes and an increase implies a worse prognosis, e.g., a high risk of clinically refractory RA or significant joint damage over the next 5 years.5,6 This helps prioritize patients in the primary care setting for rapid referral to rheumatologists and facilitate early intervention with biological therapies.
RA management and care. Testing for 14-3-3η together with ESR and CRP can aid in monitoring disease progression.
RA treatment response and monitoring. Testing for 14-3-3η levels can aid in monitoring response to treatment with disease-modifying anti-rheumatic drugs (DMARDs) or anti-TNF therapies.7,8,9
A faster evaluation for a healthier patient
14-3-3η puts more power in the hands of primary care to differentially diagnose RA. This avoids a delay in diagnosis that can occur if there is a long wait to see a rheumatologist. It also enables faster and more informed referral to a rheumatologist. In either case, evaluation that includes 14-3-3η can enable treatment to begin sooner, possibly preventing further joint erosion and leading to improved health outcomes.
Ready to learn more? Visit our Test Center for the test summary of our new integrated ANA panel, which screens and reflexes to distinguish among the 8 most common autoimmune rheumatic diseases, including RA.
1. Jansen AL, van der Horst-Bruinsma I, van Schaardenburg D, et al. Rheumatoid factor and antibodies to cyclic citrullinated peptide differentiate rheumatoid arthritis from undifferentiated polyarthritis in patients with early arthritis. J Rheumatol. 2002;29:2074–2076.
2. Maksymowych WP, Naides SJ, Bykerk V, 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;41:2104–2113.
3. Naides SJ, Marotta A. 14-3-3η in “seronegative” rheumatoid arthritis. J Rheumatol. 2015;42(10):1995.
4. Maksymowych WP, Naides SJ, Bykerk V, 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;41:2104–2113.
5. 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.
6. van Beers-Tas MH, Marotta A, Boers M, et al. A prospective cohort study of 14-3-3η in ACPA and/or RF-positive patients with arthralgia. Arthritis Res Ther. 2016;18:76.
7. Britsemmer K, Maksymowych WP, van Schaardenburg D, et al. FRI0059 14-3-3eta is an early RA biomarker that is modifiable with standard DMARDs and corresponds with improvement in clinical variables. Ann Rheum Dis. 2013;72:A388.
8. Maksymowych WP, et al. Arthritis Rheum. 2013: poster presentation.
9. Hirata S, Marotta A, Gui Y, et al. 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. 2015;17:280.