Diagnosis of Rheumatoid Arthritis
“Antibodies to cyclic citrullinated peptide may precede the unset of rheumatoid arthritis by as much as ten years,” stated William Robinson, M.D., Ph.D., assistant professor of medicine in the department of immunology and rheumatology at Stanford University.
Current treatments for the disease include small molecules such as methotrexate, hydroxychloroquine, and biologicals such as anti-TNF and anti-CD20 recombinant antibodies. Dr. Robinson’s team is developing protein arrays to ferret out new markers. “Through profiling of circulating autoantibodies and cytokines, we have identified markers with predictive utility,” he continued.
The current model of the chain of events leading to the disease ties together an adverse combination of genetic markers and potential environmental inputs, including smoking, hormones, and infections, setting the stage for the early, preclinical forms of the disease. Moreover, there are subtypes of the disease that respond differentially to the available therapies.
Part of the pathogenesis of rheumatoid arthritis may reside in citrullinated proteins that are produced by enzymatic deimination of arginine residues in proteins. This increased enzymatic activity results in an unfolding of proteins by loss of a positive charge in arginine residues, triggering an autoantigenicity cascade. This pernicious series of unfortunate events takes place in the synovial fluid within the joint cavity leading to lymphocyte invasion, production of TNF and other pro-inflammatory cytokines, production of degradative enzymes, and ultimately joint destruction.
Dr. Robinson’s team designed protein arrays in which a large coterie of antigens were printed onto microplates and then probed with patients’ antisera. Historical experience in the management of patients speaks loud and clear: early intervention with at-risk patients resulted in 56% remission. A retrospective analysis of serum samples taken from patients who later developed arthritis demonstrated that many cytokines and autoantibodies appeared prior to the onset of clinical disease, yet far and away the best prognosticator was antibodies to cyclic citrullinated peptide.
Profiling Serum Antibodies
Serametrix has developed assays for multiplex detection of serum antibodies using an array of tumor antigens, according to Henry Hepburn-Scott, Ph.D., vp, business development. These antibodies are raised by patients, so the approach is similar to the Aushon platform. The antibodies were screened against proteins that Dr. Hepburn-Scott and his colleagues had selected according to the criteria that all were associated with cancerous phenotypes, had demonstrated immunogenicity, and could serve as biomarkers for drug discovery and development. Dr. Hepburn-Scott and his colleagues used this strategy to detect tumor antigens in a cohort of 16 different patients.
Data from such studies can help to monitor immune response to drugs, give early warning of immune-related adverse events, and even provide a high-value companion diagnostic to identify responders in pre-treatment cohorts.