Biomarkers are unquestionably the most compelling topic in rheumatoid arthritis right now. Just this past June, at the annual meeting of the European League Against Rheumatism (EULAR) in Madrid, they were the focus of an unprecedented number of studies, whether directly, in the case of putative or proposed biomarkers in various stages of validation, or indirectly, as the proposed solution to problems ranging from adherence to switching to redefining early and established disease.
For some time now experts have agreed on the need for early and aggressive treatment of RA, an approach that increases the likelihood of achieving remission, reduces disability related to RA, lowers the risk for cardiovascular and other complications, and improves long-term outcomes. But while this approach has indeed begun to improve treatment, it is rapidly becoming old news. Physicians and researchers are already looking ahead, hoping that biomarkers might bring greater objectivity and precision to the treatment of RA, and in turn, more opportunities to improve overall management of the disease.
Among the most coveted biomarkers are those that would enable diagnosis of RA at earlier (and eventually presymptomatic) stages of the disease, and dynamic biomarkers that would lead to improvements over current disease assessment tools. Research in each of these areas has already yielded two commercially available tests: 14-3-3eta, a propriety protein biomarker (Quest Diagnostics) used to improve early diagnosis of the disease, and Vectra DA (Crescendo Bioscience), a multibiomarker panel that enables more objective assessment of disease activity. Yet clinicians are still eagerly awaiting the availability of additional tests.
Biomarkers might help doctors avoid using riskier therapies, says Joan Bathon, MD, editor-in-chief of Arthritis and Rheumatism.
“Of course we would like to have biomarkers that would tell us who is most likely to respond to the different treatments available,” says Joan Bathon, MD, director of the division of rheumatology at New York–Presbyterian Hospital and Columbia University Medical Center and editor-in-chief of Arthritis and Rheumatism. “And it also would be very desirable to identify patients who are likely to have more aggressive disease. If, for example, a biomarker could tell us that a particular patient’s disease is likely to be mild, we might not want to take some of the risks associated with aggressive therapy.”
Biomarkers, which have been defined as characteristics that can be objectively measured as indicators of normal or pathologic biological processes, or responsiveness to therapy, already have been used for years to assist in making a clinical diagnosis of symptomatic RA. Testing for the presence of rheumatoid factor (RF) and anticitrullinated protein antibodies (ACPA) is currently the primary means by which RA is diagnosed. However the sensitivity and specificity of these markers is limited. The next generation of biomarkers will be not only actionable but also what William H. Robinson, MD, PhD, associate professor of rheumatology and immunology at Stanford University, describes as “mechanistic,” or more firmly rooted in disease pathogenesis.
“Single biomarkers may be informative on a population level” but perhaps not so much for individuals, says William H. Robinson, MD, PhD.
“In rheumatoid arthritis,” says Robinson, “there is a tide of inflammation, meaning that many different cells and pathways and molecules become activated and elevated. In many cases those that are activated are just along for the ride, but not actually causing the disease.” From among the select number that do cause disease, researchers hope to identify mechanistic biomarkers from which they can extract valuable information that can guide clinical decision making. But regardless of new discoveries, RF and ACPA tests will continue to have value.
“It’s important to recognize,” says Robinson, “that single biomarkers may be informative on a population level, but not necessarily on the level of an individual patient.” Multiple biomarkers “are likely to give more complete information about the state of the immune system and the autoimmune process.”
A validated biomarker used in conjunction with RF and ACPA, then, might help to improve the sensitivity and specificity of diagnostic testing, and that is exactly the idea behind 14–3-3-eta, the protein biomarker that Quest Diagnostics made commercially available in 2013, under a licensing agreement with Augurex. The 14–3-3eta protein can be considered a mechanistic biomarker as defined by Robinson at Stanford, since its functions include the regulation of intracellular communication networks that are involved in inflammatory processes relevant to rheumatoid arthritis. This new diagnostic tool uses an enzyme-linked immunosorbent assay (ELISA) that can readily detect the 14–3-3eta protein in the peripheral serum of patients with rheumatoid arthritis. Because the 14–3-3eta test is based on the standard ELISA method, it is supported by most health plans under current codes.
The ability to diagnose RA at a pre-symptomatic stage could become a reality soon. Researchers have identified a combination of serum autoantibodies and cytokines that already have been used to identify asymptomatic individuals who will go on to develop RA up to two years after testing. While the prospect of such a test might be exciting, it would have limited utility in clinical practice, since screening the general population for RA is not feasible.
However, because first-degree relatives of patients with RA have a greater chance of developing the disease, there is a scenario in which this type of early diagnosis could offer value in the clinical setting.
“I might consider using such a test,” says Bathon, “if, for example, I had a patient with RA in her 60s and she expressed concern about whether her children might develop RA.”
Like many biomarkers currently in the pipelines, this diagnostic panel must undergo more testing. Progress with regard to the validation of biomarkers has been slow because of a number of hurdles, many of which can be traced to an incomplete understanding of immunology. Although there is cause for optimism, RA is unlikely to experience the kind of rapid success with biomarkers that oncology has seen, in part because so far genetic tests do not appear to be useful. While genetic traits may have some utility in RA, Robinson says the magnitude of their value isn’t sufficient to base predictive tests on them.
“In cancer,” says Robinson, “a single genetic biomarker can completely guide treatment because that single gene is causing the disease. In contrast, RA appears to be polygenic — we believe that 10 or 20 or more genes may work together to cause susceptibility to the disease.” ”