NEW YORK (GenomeWeb) – A team led by researchers at the University of Alberta and Quest Diagnostics have completed a preclinical validation study that indicates the protein 14-3-3eta is a useful biomarker for rheumatoid arthritis.
In particular, their findings suggest that the protein has potential for improving early diagnosis and for identifying severe cases of the disease, Walter Maksymowych, a medical research professor at the University of Alberta and leader of the study, told ProteoMonitor.
Quest licensed the marker from Vancouver-based Augurex Life Sciences in 2012 and began offering it commercially in February of this year as a tool for diagnosis of RA.
According to Stanley Naides, medical director, Immunology R&D at Quest and co-author of the study, which was published this week in the Journal of Rheumatology, the company has seen "vigorous" physician uptake of the test since its launch, though he did not provide specific sales figures. Quest offers the test as both a standalone assay and as part of a panel including other RA biomarkers.
In the recent study, Naides told ProteoMonitor, the researchers aimed to evaluate the specificity and sensitivity of 14-3-3eta in a cohort including not only RA patients but patients featuring a broad range of similar and related conditions, including psoriatic arthritis and ankylosing spondylitis.
Another key question, Maksymowych said, was the extent to which 14-3-3eta provided additional information beyond that offered by conventional RA biomarkers such as C-reactive protein (CRP), anti-citrullinated protein antibody (ACPA), rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), and the Disease Activity Score.
"This is a very common question from clinicians, so the study really looked at this," he said, noting that in the case of CRP and ESR, 14-3-3eta measurements did not correlate at all, while in the case of RF, adding 14-3-3eta allowed the researchers to identify an additional 30 percent of the early RA population.
"So, for these biomarkers that are typically used in primary care, the potential is here for a fairly substantial pick-up [by adding 14-3-3eta]," Maksymowych said. "14-3-3eta is giving us different information that enhances [the biomarkers] clinicians currently use."
In the study, the researchers compared 14-3-3eta levels in 75 established RA patients against a 385-subject control group that included 189 healthy subjects, 67 ankylosing spondylitis patients, 5 gout patients, 10 lupus patients, 5 scleroderma patients, 5 Sjögren's patients, 5 osteoporosis patients, 10 Crohn's disease patients, 10 ulcerative colitis patients, 10 psoriasis patients, 10 type 1 diabetes patients, 5 multiple sclerosis patients, and 24 psoriatic arthritis patients.
Levels of 14-3-3eta distinguished between RA cases and controls with a sensitivity of 77 percent and a specificity of 93 percent.
The researchers also investigated the presence of 14-3-3eta in early RA patients, measuring the marker in 99 patients with a median disease duration of 3.4 months. At this point in the disease progression, 64 percent of patients were positive for 14-3-3eta, compared to 59 percent and 57 percent that were positive for ACPA and RF, respectively.
Testing for ACPA, RF, and 14-3-3eta together, the researchers found that 78 percent of the early RA patients were positive for any one of the three markers.
Early identification and treatment is considered key to managing RA, Maksymowych said. "Clinicians are very interested in finding better ways to identify patients early on. This is important because there is evidence that if we treat very early on we may be able to alter the natural history of the disease and certainly institute appropriate personalized medicine strategies."
The researchers also discovered that 14-3-3eta appeared to be correlated with more severe forms of the disease, Maksymowych said, noting that a number of commonly used metrics of disease severity, including RF, ESR, CPR, and the Health Assessment Questionnaire – a clinical tool for assessing RA activity – are increased in the patients identified by 14-3-3eta.
While the Journal of Rheumatology study didn't look into whether 14-3-3eta can be used to guide therapy in RA patients – identifying, for instance, patients likely to respond to anti-TNFα therapy – Maksymowych said that he and his colleagues have presented preliminary data at several RA meetings suggesting that it could be useful for such a purpose.
In a 2013 interview with ProteoMonitor discussing the Quest licensing deal, Augurex CEO Norma Biln said that Augurex had performed studies investigating the protein's utility in these roles, and characterized these efforts as "close behind" the company's work establishing the protein as a marker for early diagnosis.
Perhaps the most prominent player in the RA protein biomarker arena is Crescendo Bioscience, whose 12-protein Vectra DA test is designed for measuring disease activity in RA patients and, potentially, tracking patient response to therapy. In February, Myriad Genetics acquired Crescendo for $270 million, a deal that served as a significant endorsement of both protein markers for RA and clinical proteomics more generally.
Maksymowych and Naides said, however, that they didn't view 14-3-3eta as a competitor to Vectra Da, but, rather, as a likely complement. With regard to diagnosis, Augurex and Quest have targeted 14-3-3eta as a tool for early diagnosis, while Vectra DA is intended as a tool for ongoing assessment of disease activity in established patients.
And while both tests could be useful for predicting patient response to therapy, Maksymowych said he suspected the two tests would provide different parts of the picture.
"My suspicion is that they will be complementary rather than overlapping," he said. "Vectra DA demonstrates some overlap with acute phase reactants like CRP, and we don't seem to be seeing that with 14-3-3eta. So we think that we are seeing with the different biomarkers different pieces of the entirety of the disease."
Quest offers the 14-3-3eta assay as a laboratory-developed test and currently has no plans to take it through US Food and Drug Administration 510(k) clearance.
Under its licensing agreement with Augurex, Quest holds exclusive US rights to the assay. Augurex plans to offer the test outside the US, including in Canada in the near future.