Although a combination of medications in a treat-to-target approach will work for most patients, some people are completely refractory to any therapy. “Rather than cycling through three or four treatments, a biomarker could help you pick the ideal treatment,” Dr. Rigby says. Although RA is a polygenic disorder and can be divided between seropositive and seronegative disease, “those distinctions have really not had that much power in terms of guiding therapy.”
Targets with Potential
William Robinson, MD, associate professor of immunology and rheumatology at Stanford School of Medicine (Calif.), says the objective is to “create biomarkers that are informative in different dimensions than DAS scores. DAS scores simply measure current disease activity, and we need biomarkers that can predict response to therapy.”
There are no good candidates currently for biomarkers that could be used to identify subsets of patients likely to respond to a particular therapy, but the “overarching objective is to develop such in the future.” Mechanistic biomarkers offer the greatest potential, Dr. Robinson says. In a recent article in Nature Reviews Rheumatology, Dr. Robinson and colleagues explained that a mechanistic biomarker is directly involved in the pathogenesis of a disease, enables differentiation of distinct subtypes of the same disease, can be used to stratify disease and target treatment, and could indicate whether a therapy is targeting the cause of a disease.1
In rheumatology, defining a new molecular taxonomy of disease and the subsequent identification of diagnostic, predictive and prognostic mechanistic biomarkers begins with first stratifying current clinical classifications and identifying molecular pathways that mediate the pathogenesis of disease, they wrote.
“We anticipate that involvement of certain molecular pathways will be shared across subsets of multiple different rheumatic diseases, whereas other pathways will be disease specific. Molecular classification of disease could enable the identification of disease subtypes that are responsive to specific therapeutics and eventually the use of patient-derived biomarkers for guiding target therapy,” they said.
Incremental research is underway to identify mechanistic biomarkers that may one day guide therapy. A study by Dennis and colleagues in Arthritis Research & Therapy used genome-wide expression analysis of synovial tissues from a large RA cohort to look for potential biomarkers.2 The researchers used a combination of global gene expression, histologic and cellular analyses, and analysis of gene expression data. That research defined molecular and cellular phenotypes that reflect the wide heterogeneity present in RA synovium.