Rheumatoid arthritis genetic link explains severity

The question of why some people are genetically predisposed to rheumatoid arthritis has been answered for some patients by Canadian researchers.

The question of why some people are genetically predisposed to rheumatoid arthritis has been answered for some patients by Canadian researchers.

Rheumatoid arthritis is a debilitating joint disorder that affects about one per cent of the population. It is an autoimmune disorder that causes the body's immune system to attack itself. 

More severe rheumatoid arthritis is linked with a certain gene mutation, researchers have found. (iStock)

For about 10 years, researchers have been looking for genetic causes of the disease to improve treatments.

In Sunday's issue of the journal Nature Genetics, a team of scientists from Toronto and Montreal answered the question of why people with an altered gene end up getting the disease.

To find out, lead author Dr. Kathy Siminovitch, a professor in the department of medicine at the University of Toronto, and her co-authors studied mice with a mutation in gene PTPN22 and then validated the findings using blood samples from humans with the disease and healthy controls.

Normally, the gene makes a protein that suppresses immune cell responses, said Siminovitch, who also works at the Samuel Lunenfeld Research Institute at Mount Sinai Hospital. But in people with rheumatoid arthritis with the changed gene, the protein almost disappears and the immune response becomes too high.

"We see our research as a circle," Siminovitch said. "It starts with the patient because we get their blood. Then it goes into our lab. Then we want to take it right back to the patient again and deliver it as something that's useful to them."

The investigators aren't there yet, since many genes contribute to rheumatoid arthritis. But the findings open the door to sorting out the connection between other genes and the disorder, she said.

Toward personalized treatment

Researchers have been trying to work out how this gene mutation impairs immune cell function for about five years. It took the mice model to make it clear, and then the team knew what to look for in humans.

Preliminary data suggests those with the mutation will get more severe disease. That's important to know, because there are effective new drugs for rheumatoid arthritis but they are costly and can have significant side-effects.

For "one of our front-line drugs that every patient gets if they have rheumatoid arthritis, about one-third are getting no response or they're not going to get a good response. It takes us six months to a year to really see that, and we just wasted a year of that patient's time where their disease might have been progressing because they didn't respond to that drug."

With the new discovery, doctors are a step closer to being able to tell which patient will respond to a particular drug after a simple blood test that takes a day or two.

"Measuring levels of this protein will help us monitor disease severity in patients with autoimmune disorders, test the effects of various therapies including new drugs, and determine which treatments work best in specific patients," said Dr. Edward Keystone, co-author of the study and director of the Rebecca MacDonald Centre for Arthritis and Autoimmune Disease at Mount Sinai Hospital.

Before the test can be used clinically outside of the research lab, its accuracy and reliability need to be confirmed.

The blood test is not too expensive and is expected to become more economical as it is used more widely, Siminovitch said.

The study was funded by the Canadian Institutes of Health Research, the Canadian Arthritis Network and the Ontario Research Fund.

With files from CBC's Amina Zafar