New RA Test Launched Ahead of Visible Evidence for Benefit

Quest Diagnostics is promoting a new blood test that combines a novel biomarker, 14-3-3eta, with tests for two well-established markers for rheumatoid arthritis (RA)  – cyclic citrullinated peptide (CCP) antibodies and rheumatoid factor (RF) – as a better way to identify and treat RA early enough to prevent joint damage and progression. The new biomarker is a regulatory intracellular protein that activates pro-inflammatory cytokines.

The test has been released via a regulatory pathway that does not require clinical proof of efficacy. A rheumatologist independent of its development advises waiting for more validation before using the test or acting on it.

Quest cites abstracts of conference presentations as evidence that its proprietary biomarker outperforms both RF and CCP antibody testing. Stanley J. Naides MD of Quest’s Nichols Institute points to a study presented at the 2011 American College of Rheumatology meeting, which was conducted among 74 early RA patients from three study cohorts and 50 patients with osteoarthritis as controls. He said that an ELISA for 14-3-3eta was positive in 60-82% of patients, at least equivalent to RF alone (32-82%) and to CCP antibody alone (44-82%).  Combining the three markers increased sensitivity for early RA to 72%-100% of the patients, said Naides, who is Medical Director of Immunology Research and Development and Interim Scientific Director of Immunology R&D at the Institute.

Naides said the complete information is being prepared for submission to a major rheumatology journal.

According to background supplied by Quest, 14-3-3eta is one of seven members of a family of intracellular chaperonins and is present in the synovial fluid as well as in the serum of patients with RA and psoriatic arthritis.

“From an in vitro standpoint, it looks like 14-3-3eta is contributing to disease by up-regulating several inflammatory and joint damage factors,” explained Anthony Marotta, PhD, chief scientific officer for Augurex Life Sciences Corp. of Vancouver, which licensed the biomarker to Quest Diagnostics.  “We find that patients with high levels of this protein have more erosive disease, and their disease burden is higher.”
 
Preliminary research suggests that 14-3-3eta up-regulates the matrix metalloproteinases MMP-1 and MMP-3, both drivers of joint erosion. “Early studies also indicate that 14-3-3eta expression can induce cytokines like TNF-α,” Marotta said. "We also see that 14-3-3eta is partly down-regulated with anti TNF-α drugs. Clinical data presented at rheumatology conferences show that at 15 weeks post-treatment with adalimumab, if levels of 14-3-3eta drop, patients do better.”

Michael Lockshin MD, director of the Barbara Volcker Center for Women and Rheumatic Disease at the Hospital for Special Surgery in New York, cautions that it is too early to judge the test’s prognostic value.

“The research I have seen shows only modest improvements in specificity; it is basically a refinement of CCP testing,” said Lockshin, who is a professor of medicine at the Weill Cornell Medical College.

“We need to know whether people can have a positive14-3-3eta test months or years before they show clinical signs,” he added. “Given the risks and side effects of the current aggressive biological treatments, right now I see no benefit in ordering the test for asymptomatic patients.”

Quest has licensed rights to 14-3-3eta as a Laboratory Developed Test (LDT) in the US, along with a panel that also measures CCP and RF. Naides says that many tests in use by rheumatologists have been licensed as LDTs. Under the Clinical Laboratory Improvement Act (CLIA), an LDT is required only demonstrate its performance in the lab and that its methodologies provide quality results. For FDA approval, clinical evidence that the test can actually identify or predict RA would be required.