Researchers Define Autoantibody-Producing Role of B-Cells in RA

The results of a recently published paper suggest that clinical trials for new rheumatoid arthritis drugs should shift from their sole focus on relieving inflammation to eliminating the B-cells that produce the anti-citrullinated protein antibodies that are the cause of the disease.

Anti-citrullinated protein antibodies (ACPAs) are autoantibodies that are directed against peptides and proteins that are citrullinated. During inflammation, arginine amino acid residues can be enzymatically converted into citrulline residues in proteins such as vimentin, by a process called citrullination. If their shapes are significantly altered, the proteins may be seen as antigens by the immune system, thereby generating an immune response. ACPAs have proved to be powerful biomarkers that allow the diagnosis of rheumatoid arthritis (RA) to be made at a very early stage.

In RA, autoreactive B-cells are pathogenic drivers and sources of ACPAs that serve as a diagnostic biomarker and predictor of worse long-term prognosis. Yet the immunobiologic significance of persistent ACPA production at a cellular level is poorly understood.

Investigators at the New York University Langone Medical Center used an ELISA and a sensitive multiplex bead-based immunoassay to characterize fine-binding antibody-specificities in sera, synovial fluid (SF), and B-cell culture supernatants from RA patients and normal control subjects.

The investigators reported in the January 24, 2017, online edition of the journal Arthritis & Rheumatology that they found high levels of APCA-secreting memory B-cells in the blood of patients with these autoantibodies, but not in patients without autoantibodies or in the healthy volunteers. APCA levels were directly proportional to the recirculating memory B-cells in the blood stream, confirming that current drug treatments do not affect the underlying autoimmunity in rheumatoid arthritis.

"We have developed a test for measuring the underlying autoimmunity in rheumatoid arthritis patients that should be used to evaluate new treatment regimens," said senior author Dr. Gregg Silverman, professor of medicine and pathology at the New York University Langone Medical Center. "We believe this provides a road to a cure for rheumatoid arthritis. We need to develop longer-term vision of how to improve the treatment of rheumatoid arthritis. This new tool may show that agents that target other molecules or cells have advantages that were previously not considered now that we can better measure those effects."