A new study led by researchers at The Walter and Eliza Hall Institute of Medical Research and the University of Melbourne in Australia recently revealed a link between rheumatoid arthritis (RA) and heart valve disease, based on a key inflammatory protein. The study was recently published in the journal Proceedings of the National Academy of Sciences (PNAS) and is entitled “Spontaneous retrotransposon insertion into TNF 3′UTR causes heart valve disease and chronic polyarthritis”.
RA is an autoimmune disease that leads to chronic inflammation of the joints and other parts of the body due to an overreaction of the body’s own immune system, resulting in the attack of healthy tissues. The disease can cause painful deformity and immobility of the fingers, wrists, ankles and feet, being more common among women. Heart disease is also a frequent feature associated with RA, a condition estimated to affect approximately 2% of the Australian population.
It has been previously reported that RA patients produce great amounts of the inflammatory protein called tumor necrosis factor (TNF). TNF is known to recruit immune cells, resulting in joint damage and the induction of a continuous state of inflammation. Now researchers have found a link between inflammation and TNF overproduction, and the development of rheumatoid arthritis and heart valve disease.
Interestingly, by using animal models, the research team identified a DNA region in the TNF gene that impairs its normal regulation resulting in its over-production, leading to inflammation, polyarthritis (any type of arthritis affecting five or more joints simultaneously) and heart valve disease. Furthermore, the team also identified several specific zinc-finger proteins able to regulate TNF protein expression.
“People with rheumatoid arthritis have too much TNF in their joints and in their blood,” said the study’s senior author Dr. Philippe Bouillet in a news release. “We have identified a previously unknown way that the body destabilizes the molecules during the process of TNF production to stop too much of the protein being made. We could essentially develop agents that put a spanner in the works, stopping the factory production of TNF.”
According to the researchers, treating RA patients with drugs able to control the excess of TNF protein in the body has been shown as an effective strategy to manage the disease. However, “Up to 50 per cent of patients become unresponsive to anti-TNF drugs because they develop immunity to this foreign protein,” explained Dr. Bouillet. “We think targeting the regions of the DNA that destabilize the molecule could be an innovative way to interfere with protein production to dampen the amount of TNF being made.”
“This is the first time that we have linked the overproduction of TNF to heart valve disease,” noted Dr. Bouillet. “While it seems that genetics makes a substantial difference to the severity of the heart disease in our models, it does suggest that in humans we may be able to better diagnose heart valve disease in people with rheumatoid arthritis in the future.”
The team concluded that this is the first animal model demonstrating that polyarthritis and heart disease can result from TNF deregulation, and suggest that drugs able to block and remove TNF, and consequently reduce inflammation, could be investigated as a therapy for heart valve diseases. “Clinicians have trialled drugs that target TNF in the past, but for diseases of the heart muscle and with poor effect,” said Dr. Bouillet. “Our studies suggest that excessive TNF drives heart valve – rather than heart muscle – diseases, and may be worth investigating for inflammatory diseases affecting the heart valves, such as rheumatic heart disease.”