“We know that autoantibodies are present in most people who develop autoantibody-positive RA months or even years before they develop any sign of joint disease. “Something had to happen prior to this,” says Dr. Demoruelle.

“Some event, which could be an environmental exposure like smoking or an infection, in a person with the appropriate genetic factors may lead to the development of autoimmunity and, eventually, the symptoms of RA,” she explains.

The team has found that people without RA who have the high-risk autoantibodies are much more likely to have evidence of inflammation in their lungs than people without RA who do not have the high-risk autoantibodies. These findings suggest that there is something happening in the lungs in the preclinical period, and the group is trying to figure out what it is and what it means.

“Our goal is to look closer at the mechanisms of RA development to see if there is something occurring in the lung that could be involved in starting the disease,” explains Dr. Demoruelle.

Dr. Mikuls acknowledges that researchers still have many questions about the mechanistic links between cigarette smoke and development of RA.

“We know they are associated, but we don’t know all the steps or how they fit together,” says Dr. Mikuls. “Many hypotheses are being explored, such as involvement in the lung, increased citrullination of proteins caused by cigarette smoking and stronger autoantibody responses to these proteins in people who carry the HLA genetic risk factors. And those are just some steps we think we know. There are a lot of fine details between those steps we haven’t gotten to.”

Could Avoiding Smoke Exposure Prevent RA?

A big take-home message from the many large gene-smoking studies, particularly a large study in Sweden, is that smoking is a major preventable risk factor for RA. The Swedish research suggests that 20 percent of cases of RA overall and 35 percent of cases of ACPA-associated RA are due directly to smoking. When the researchers looked just at ACPA-associated RA, they estimated that 55 percent of cases involving two copies of the SE gene are due directly to smoking.

“That’s pretty amazing if you think about it,” says Dr. Mikuls. “If you could abolish smoking as an environmental hazard, you could get rid of one in five new cases of RA. If you went to the population of people with two copies of the shared epitope gene and could abolish smoking, you would eliminate one in two new cases of RA. That’s amazing.”

Whether avoiding second-hand smoke also could help prevent RA in genetically predisposed people is unknown.

“We don’t know if second-hand smoke is a risk factor for RA, but this is a great question,” says Dr. Demoruelle. “Unfortunately, our ability to study this question is limited by the fact that it is extremely difficult to classify how much second-hand smoke a person has been exposed to.”