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Chemical shows promise in subduing joint inflammation in rheumatoid arthritis

February 16, 2017

By Mike Richman
VA Research Communications

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Some 1.5 million Americans, including many Veterans, are estimated to have rheumatoid arthritis. (©iStock/JodiJacobson)

Some 1.5 million Americans, including many Veterans, are estimated to have rheumatoid arthritis. (©iStock/JodiJacobson)


Rheumatoid arthritis affects about 1.3 million Americans, including many Veterans. It's an autoimmune disease in which the body's immune system mistakenly attacks its own joint tissue. The joints of the hands, feet, wrists, elbows, knees, and ankles can become seriously inflamed, causing stiffness and throbbing pain.

Most treatments work by broadly removing or inhibiting molecules that play a role in inflammation. Immune cells release the molecules when harmful agents invade the body.

Instead of trying to suppress the latter stages of the inflammatory process with drugs, however, one group of VA researchers is taking a more proactive approach, with the understanding that early treatment is critical. They've tested a chemical compound that works to prevent an initial phase of tissue inflammation and improve one's immune system.

"We're excited that we are making progress to understand how rheumatoid arthritis develops so that we can cure and prevent it," says co-researcher Dr. Jorg Goronzy, a rheumatologist at the VA Palo Alto Health Care System in California.

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(©iStock/ttsz)

(©iStock/ttsz)


Multiple benefits to immune system

In this case, improvements in human system function mean the ability of a person to recover from inflammation, while also being able to fight infection; respond to vaccines; and identify and remove tumor-related cells, according to Goronzy and his research team. In addition, the rate of developing cancer declines by at least twofold due to treatment with the chemical, compared with a person who is not treated, they write.

Lab studies have suggested the compound, which is under a U.S. patent, might improve immune system function in patients with rheumatoid arthritis. In that condition, naïve lymphocytes, mature immune cells that have not been exposed to an antigen, endure elevated amounts of DNA double-strand breaks, a sign of genetic instability. That pattern is often seen in people with rheumatoid arthritis, the recipients of bone marrow transplants, and adults age 50 or older.

"If this line of treatment can be further developed, many Veterans will benefit."

Goronzy and Dr. Cornelia Weyand, another rheumatologist at the Palo Alto VA, led the lab testing. The two also hold academic appointments at Stanford University. Their team has used a human-mouse "chimera" model in which synovial tissue, which lines the cavities of joints and creates a fluid that helps the joints move smoothly, is taken from people with rheumatoid arthritis and implanted into a mouse. Goronzy explains that the chimera model is a valid lab technique for studying human disease because it involves human tissue, with the mouse acting only as a carrier.

Chemical stops cells from dying

The researchers found in the tissue that T cells—lymphocytes that play a key role in protecting the human immune system—have trouble repairing the damaged DNA. In response, the cells activate an enzyme that induces inflammation.

The treatment calls for administering a chemical agent that restrains the enzyme and thereby improves the ability of the T cells to repair the DNA, thus reducing inflammation. The agent, ethanone, works to stop a DNA-dependent protein (DNA-PKcs) from causing apoptosis, a form of cell death. This increases the viability and diversity of naïve lymphocytes in the tissue of people with rheumatoid arthritis, according to the researchers.

Goronzy says other research teams have studied the link between DNA damage and inflammation, but that his was the first to explain how the enzyme DNA-PKcs plays a role in the development of rheumatoid arthritis. Other chemicals besides ethanone can have similar effects in subduing DNA-PKcs, he adds.

More recently, in December 2016 , Goronzy and Weyand published an article in the Annals of the American Thoracic Society reaffirming how efforts to counter aging and weakening of the immune system should focus on extending T cell survival while curbing the type of generalized—and non-helpful—inflammation that often increases as people grow older.

The U.S. Patent and Trade Office approved ethanone as a method to boost immune function in December 2016. VA jointly owns the patent with Stanford. VA's Technology Transfer Program, which often assists VA researchers in obtaining patents, helped with the process.

The lab testing has been done at the Palo Alto VA and at Stanford. Although mice were used, Goronzy is confident the treatment will work in humans because the pathway contributing to the disease was linked to T cells from people with rheumatoid arthritis. "Thus, we know that this pathway is activated in patients," he says.

At the same time, Goronzy says "significant development" is needed before ethanone can enter the clinical testing phase. Any further development will depend on finding a commercial partner, he notes. It's unknown what side effects the chemical may cause, and it's too early to predict if and when the Food and Drug Administration will approve it, he says.

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Veterans as a group have a high prevalence of rheumatoid arthritis, which can destroy cartilage and bone, increase one's risk for cancer, and even lead to death. A 2013 study by the Centers for Disease Control found that 25 percent of Veterans have arthritis, and that arthritis is more common among Veterans than non-Veterans across all socio-demographic categories, whether defined on the basis of sex, age, fitness level, employment status, or household income. There are more than 100 types of arthritis and related conditions. More than 50 million Americans have the disease, including 27 million with the most common form of arthritis, osteoarthritis, and 1.5 million with rheumatoid arthritis.

In 2015, VA researchers found that men with rheumatoid arthritis have double the risk of death from all causes and triple the rate of death from respiratory causes—compared with men without the disease.

"Rheumatoid arthritis is one of the most frequent autoimmune diseases in Veterans," Goronzy says. "If this line of treatment can be further developed, many Veterans will benefit."


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