Two new studies have identified an association between smoking and the development of autoantibodies and suggest that rheumatologists should include smoking cessation efforts as part of a comprehensive care program for patients with autoimmune diseases. One report found that current smoking is a risk factor for the development of double-stranded DNA (dsDNA) autoantibodies in patients with systemic lupus erythematosus (SLE),1 and the second study found that smoking is a strong risk factor for rheumatoid nodules in early rheumatoid arthritis (RA).2 Both studies were published in the May issue of Annals of the Rheumatic Diseases.

This research "is a call for further mechanistic studies to [clarify the] proposed link that smoking products form DNA adducts and that these adducts cause the autoimmune responses," says Dr. Mikuls.
The first study identified a strong association between smoking and the development of autoantibodies to dsDNA. Specifically, current smokers were more likely to be dsDNA seropositive compared with former smokers and people who have never smoked (odds ratio [OR] = 3.0 and 4.0, respectively). Moreover, the findings remained significant after adjustment for sex, age at SLE diagnosis, amount smoked, age when smoking began, and the time since smoking cessation for former smokers.

Potential new mechanism described for development of autoantibodies

It is not yet clear how smoking is linked to dsDNA seropositivity, but the authors of the first study suggest that the association may be explained by the formation of DNA adducts caused by the metabolism of tobacco smoke with resultant autoantibodies to the damaged DNA. "It is possible, for example, that in some patients with SLE DNA adducts serve as the antigen for the formation of dsDNA autoantibodies or, possibly, antibodies to DNA adducts act as anti-idiotypes for the formation of dsDNA autoantibodies," write the researchers, led by Michelle Freemer, MD, of the University of California in San Francisco.

"The hypothesis that [Freemer, et al] put forward is really intriguing, although there is little data to back it up at this point," comments Ted R. Mikuls, MD, a rheumatologist at the University of Nebraska Medical Center in Omaha. "It is a call for further mechanistic studies to [clarify the] proposed link that smoking products form DNA adducts and that these adducts cause the autoimmune responses," he says.

Smoking increases risk of rheumatoid nodules in early RA

In the other study, 86% of the current and former smokers had rheumatoid nodules, compared with 59% of their counterparts who never smoked. In addition, patients with rheumatoid nodules were more likely to be rheumatoid factor (RF) positive (OR = 4.0, P <.001) than controls. RA patients who reported ever having smoked were more than seven times as likely to have rheumatoid nodules (OR = 7.3, P = .001) and this risk was not dose-dependent when smoking duration and amount smoked were tallied. Lastly, a stratified analysis showed that only smokers who were seropositive for rheumatoid factor had an increased risk for rheumatoid nodules. It is not yet understood how smoking affects rheumatoid nodules, but the researchers speculate that it may be mediated through increased RF production.

Studies underscore the importance of smoking cessation

In an editorial accompanying the two studies,3 Darcy S. Majka, MD, a rheumatologist at Northwestern University's Feinberg School of Medicine in Chicago, Illinois, and V. Michael Holers, MD, a professor in the integrated department of immunology at the University of Colorado Health Sciences Center in Denver, point out that "exposure to tobacco has consistently been associated with RA and other autoimmune diseases; therefore, studies are warranted to further define its relationship with SLE-related antibodies as well as disease development and clinical course." In addition, "because autoantibodies to dsDNA may affect disease course in SLE, smokers with SLE should be counseled to stop smoking. This is perhaps the most clinically relevant point to be gained from this article."

Dr. Mikuls agrees that "patients should quit smoking, but it is also an opportunity to learn a lot more about the mechanisms that underpin [the development of autoantibodies]. We often get very focused on disease itself and don't address behavioral issues as forcefully as we ought to. Smoking cessation needs to be part of a more comprehensive approach with these patients" he says.

References

  1. Freemer MM, King TE Jr, Criswell LA. Association of smoking with dsDNA autoantibody production in systemic lupus erythematosus. Ann Rheum Dis. 2006;65:581-584.
  2. Nyhäll-Wåhlin B-M, Jacobsson LTH, Petersson IF, et al. Smoking is a strong risk factor for rheumatoid nodules in early rheumatoid arthritis. Ann Rheum Dis. 2006;65:601-606.
  3. Majka DS, Holers VM. Cigarette smoking and the risk of systemic lupus erythematosus and rheumatoid arthritis. Ann Rheum Dis. 2006;65:561-563.