The gold-standard autoantibodies used to diagnose seropositive rheumatoid arthritis may be in for an update. Emerging data suggests that antibodies and antibody reactivities in RA are far more complex than simply the presence or absence of rheumatoid factor (antibodies against IgG) and anti-CCP, a surrogate for anti-citrullinated protein antibodies (ACPAs).
“Rheumatoid factor has been used for many decades clinically, although we know that it is not specific for RA,” said Miriam Shelef, MD, PhD, associate professor of medicine at the University of Wisconsin. “Anti-CCP is more recent, and it, too, binds to multiple different targets. Basic science that is developing now could help us develop better diagnostics.”
Dr. Shelef will explore the growing understanding of rheumatoid factor during Antibodies in RA: Beyond Citrullination & Back to Rheumatoid Factor on Friday from 12 – 1 pm EST. The initial showing will feature a live question-and-answer session. Registered annual meeting attendees also can access the session on demand until March 11, 2021.
Caroline Grönwall, PhD, associate professor of medicine at the Karolinska Institutet Center for Molecular Medicine in Stockholm, Sweden, will discuss the latest findings in antibodies to citrullinated proteins and other modified protein targets in the setting of RA.
“Citrulline reactivity is a part of defining RA, but there is a wide range of proteins that can be modified by citrullination,” Dr. Grönwall said. “In addition, there are other types of auto-reactivity in RA like anti-carbamylated proteins and we also see quite a bit of acetylation reactivity.”
It now appears that citrullinated proteins are one of several post-translational modifications targeted by a variety of multi-reactive autoantibodies in RA. What this growing category of anti-modified protein antibodies, or AMPAs, ultimately means for RA diagnosis and treatment is not yet clear, but changes to clinical practice could be on the way.
Rheumatoid factor, an antibody that binds to other antibodies, remains a mystery, Dr. Shelef said. In humans, rheumatoid factor can develop in response to inflammation following vaccination and infection, but the role it plays remains unclear. In some cases, rheumatoid factor appears to fight infection by clearing pathogens already bound to their antibody. This ability to inactivate a virus-antibody complex has been demonstrated in test tubes, but not in animals or in humans.
The role rheumatoid factor plays in the pathogenesis of RA is also unclear, although it likely potentiates the inflammation initiated by ACPAs. However, all the ways by which ACPAs and rheumatoid factor synergize are still emerging. Interestingly, new evidence indicates that some antigens could be bound by both ACPAs and rheumatoid factor potentially unifying these two antibody types.
“We have cloned the B cell receptor from single B cells from RA patients so we can characterize their reactivities in more detail,” Dr. Grönwall said. “We are seeing ACPA clones from different patients that all are multi-reactive to citrullinated protein in different patterns, and some react also to carbamylated and acetylated antigens. The monoclonal antibodies with different reactivity profiles have different functionalities, which may mean something in the patients’ disease, because these clones all came from RA patient tissues.
“Certain multi-reactivities may be more important in the disease, something in the pathogenesis that we hadn’t understood before. We may want to look a bit beyond only the CCP and rheumatoid factor reactivity.”