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Taming Supercharged Antibodies in Rheumatoid Arthritis

Date: October 1, 2013

Erika Darrah has found a unique set of antibodies in RA patients that bind to an enzyme and contribute to more disease.
Erika Darrah has found a unique set of antibodies in RA patients that bind to an enzyme and contribute to more disease.

A new finding by Johns Hopkins rheumatologists provides insight into how the immune system may increase joint damage in cases of severe rheumatoid arthritis (RA).

Studying blood samples from RA patients, researcher Erika Darrah and colleagues found a set of unique antibodies that bind to an enzyme called PAD4, which normally modifies proteins in the body to change their function. For reasons still unknown, proteins modified by PAD4 and similar enzymes can become targets of the immune system in RA.

When the novel antibodies, called PAD3/PAD4 cross-reactive autoantibodies, bind to PAD4, they supercharge it, enabling it to function 500 times stronger than normal. The work was published earlier this year in the journal Science Translational Medicine.

“PAD4 can be thought of as a fuel pump, providing fuel for the fire that is the ongoing disease in RA,” Darrah says. “When the autoantibodies bind to PAD4, it seems to change the way PAD4 functions. We think the antibodies turn on PAD4, generate much more fuel and therefore contribute to more severe disease.”

Darrah and colleagues found the aggressive antibodies in 18 percent of one set of blood samples from 44 RA patients, and 12 percent of a second set of 194 samples. In both groups, only patients with the most severe form of RA, which is accompanied by bone destruction, displayed the antibodies.

Some 80 percent of patients with the antibodies saw their disease worsen over the following year, even though they were treated with normal therapies, Darrah says.

By contrast, only 53 percent of those without the antibodies showed disease progression. And, patients with the antibodies experienced a level of deterioration of joints and bones nearly seven times that of patients without the antibodies.

Detecting the antibodies could help physicians identify patients with severe RA earlier, leading to improvements in patients’ health, says senior study investigator Antony Rosen, director of rheumatology: “These patients could start aggressive drug therapy immediately and find the most effective treatment option.” About a third of the more than 3 million Americans who have RA—mostly women—have an aggressive form.

Additionally, Darrah says, the results “suggest that drugs inhibiting the PAD4 enzyme may have real benefits in patients with severe RA and represent an important field of study for investigating new and alternative treatments.”

The team is planning long-term monitoring of arthritis patients to find out when the antibody first appears in the blood and when intervention may have the strongest impact.

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