Rheumatoid arthritis is a chronic, progressive, and debilitative autoimmune condition. It affects the joints of the body and can result in extra-articular manifestations that impact the lungs, heart, and eyes.¹ The etiology of the disease is multifactorial in nature, the understanding of which has resulted in the development of pathway-specific drugs and led to an expanded armamentarium of diagnostic and prognostic markers.² These advances continue to support clinical strategies centered on very early diagnosis, tight treatment control to achieve clinical and radiographic remission, and achieving stable drug-free disease.³ Despite these efforts, there remains a substantial unmet need for early rheumatoid arthritis (RA) diagnosis, ongoing prognosis, and remission management to optimize patient outcomes.
The 14-3-3η blood test, one of the most widely used autoimmune diagnostic tests among all other novel autoimmune tests launched in the US within the past decade, not only predicts the development of RA⁴ in its earliest stages but also provides biological information along the disease course that enables tight treatment control.⁵˒⁶ Below, we describe its use.
About the 14-3-3η Protein Blood Test
The 14-3-3η family of proteins comprises seven distinct isoforms that are critical to the regulation of intracellular functions such as protein trafficking and cellular signalling.⁴ The 14-3-3 (eta) ƞ isoform is released extracellularly in the surrounding synovial fluid and peripheral blood through specific inflammatory joint-derived processes.
In RA, 14-3-3η positive status can detect disease at a very early stage and assist with referral within 6 to 12 weeks of symptom onset. Rheumatoid factor (RF) and cyclic citrullinated peptide (CCP) demonstrate 57% and 59% sensitivity, respectively, vs. 64% for 14-3-3η.⁷ The test measures the serum levels of the 14-3-3ƞ protein that potentiate biochemical disease processes that cause joint damage in RA⁸˒⁹ and other autoimmune conditions¹⁰ with concomitant joint involvement. Combining 14-3-3η with RF and anti-CCP increases physicians’ confidence in identifying patients with RA.
“The credibility of the test is high,” wrote Walter Maksymowych, MD, FRC (C), professor of medicine, division of rheumatology, University of Alberta, Canada.¹¹ The test has been broadly published on over the past decade, including in a recent NHS systematic review.¹² Meta-analysis revealed a pooled sensitivity of 73% (95% CI: 71–75) and a pooled specificity of 88% (95% CI: 87–90).
The 14-3-3η blood test is currently available for ordering in the US through Quest Diagnostics and LabCorp as a standalone test or as part of various panels with other autoimmune markers. The 14-3-3η blood test is covered by CMS and health insurance providers.
Challenges with Early Diagnosis of Rheumatoid Arthritis
It is well established that early identification and treatment of patients with RA, within the first 12 weeks from symptom onset, can help to increase the likelihood of achieving drug-free remission.¹³ Delays in diagnosis in this “window of opportunity” often result in the loss of the golden time when treatment must start.¹⁴˒¹⁵ Differential assessment can be difficult, as patients present with nonspecific symptoms involving pain and stiffness, and may overlap with symptoms of other common joint disorders such as osteoarthritis.¹⁶
Lab testing matters, but serological and acute phase reactants have some limitations:
C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are general inflammatory markers that are not specific to RA¹⁷
RF, a legacy test, has low sensitivity and specificity¹⁸
CCP, albeit highly specific for RA, is negative in many RA patients¹⁸
28% to 44% of patients with RA are seronegative for RF¹⁹ and CCP, which means that RA patients can be frequently overlooked
At the earliest stages of disease, the 14-3-3η blood test can detect the transition to synovitis in arthritis patients,²⁰ complementing the markers listed above, and thereby enabling referral within the window of opportunity for treat-to-target strategies.
“14-3-3ƞ is found positive in two thirds of patients with early RA”, said Ara Dikranian, MD, rheumatologist with the Cabrillo Center for Rheumatic Diseases, San Diego. “If you combine a positive RF or a positive CCP with a positive 14-3-3ƞ, this increases the sensitivity greatly so there’s a lot more diagnostic certainty.”²¹
As noted, in early rheumatoid arthritis, RF and CCP demonstrate 57% and 59% sensitivity, respectively, vs. 64% for 14-3-3η.⁷ Importantly 14-3-3η captured a complementary 20% more RA patients than each of the standard tests alone.⁷ 14-3-3η’s role in the pathophysiology of disease explains why its expression in blood is clinically relevant, at the earliest stages of disease. This understanding has been advanced by examining 14-3-3η expression in pre-disease in first degree relatives (FDR) of people with RA for the development of synovitis.²⁰ 14-3-3η positivity occurred at or near the time of disease onset as a predictor of imminent RA.
Using the test in combination with standard assessments enables in-depth clinical assessments and monitoring.⁷ Timely RA diagnosis further reduces the economic burden of disease and improves physical function and productivity.
Advantages of Use of 14-3-3ƞ Test
In contrast to RF and CCP, 14-3-3ƞ is a modifiable marker whose levels substantively change along the course of disease, thereby marking dynamic disease processes. 14-3-3ƞ can be tested serially for disease monitoring and treatment modifications.²²
A decrease in 14-3-3η marks a positive response to DMARDs and anti-TNF drugs with better clinical outcomes. An increase implies a worse prognosis indicating that more joint damaging molecular processes are underway, supporting tight treatment control decisions. High levels of 14-3-3ƞ and CRP at baseline and during treatment represent a worse patient prognosis that is more likely to result in joint damage progression.²³
“At each time point, patients who were positive for 14-3-3ƞ had worse radiographic changes,”21 said Dr. Dikranian, MD, in a webinar. “Clinical remission was more likely in patients who were negative for 14-3-3ƞ.”
Importantly, even in patients who achieve clinical remission, sustained or increased 14-3-3ƞ levels mark an increased risk of radiographic progression.²³
Practical Takeaways
Outcomes in RA patient management have improved over the past 15 years. With emerging blood tests such as 14-3-3η, there is an opportunity to assist with optimizing RA patient outcomes. Overall, the 14-3-3ƞ blood test can help physicians identify people who are at risk of developing RA and follow them to optimize their treatment outcomes before any joint damage progression occurs.
Disclosures: Dr. Maksymowych was one of the co-inventors of the 14-3-3η biomarker developed at the University of British Columbia. He does not have any financial ties to lab testing companies using the test.