Novel Antibodies Identified for Severe Rheumatoid Arthritis

Cross-reactive autoantibodies could serve as the basis for the first antibody-specific diagnostic test to distinguish those with severe rheumatoid arthritis from those with less aggressive forms of the disease.
Novel antibodies to peptidylarginine deiminase 4, or PAD4, a key enzyme widely considered a possible trigger of rheumatoid arthritis (RA), have been found in blood samples from people with aggressive inflammation and connective tissue damage.

Medical scientists at Johns Hopkins University (Baltimore, MD, USA) obtained sera from 36 healthy controls, 30 psoriatic arthritis patients, and 44 RA patients from a convenience sample and from 194 patients from a longitudinal cohort study. The team used various methods to characterize the antibodies, including immunoblotting, immunoprecipitation and blocking, antibody depletion by enzyme linked immunosorbent assay, and citrullination and cleavage assays. The recombinant proteins used in the study were obtained from New England Biolabs (Ipswich, MA, USA).

The investigators found the antibodies greatly increase PAD4 enzyme function at the low levels of calcium normally present in human cells. The results showed that PAD4 activity was 500 times greater in the presence of antibodies than when they were absent. The antibodies were present in 18% of 44 fluid samples from one collection and in 12% of another collection of 194, but only in people with severe cases of rheumatoid arthritis.

In a follow-up study, 80% of patients with the antibody saw their disease worsen over the previous year, while only 53% without the antibody showed disease progression. In comparing average scores of disease-damaged joints, the scientists found that those with the antibody had an average deterioration in joints and bones by a score of 49. Those without the antibody had an average degradation in their score of 7.5, indicating a much milder disease.

Antony Rosen, MD, the senior author of the study said, “Identifying early on a subset of patients with severe rheumatoid arthritis could benefit their health, as these patients could start aggressive drug therapy immediately and find the most effective treatment option.” The authors concluded that they had identified an antibody marker that is associated with more erosive disease and markedly augments the function of a key pathogenic enzyme (PAD4) under physiological conditions. These cross-reactive antibodies may therefore identify RA patients in whom PAD inhibition would be particularly beneficial therapeutically. The study was published on May 22, 2013, in the journal Science Translational Medicine.