Smoking increases COX-2 and triggers RF expression

Janis Kelly

January 26, 2005

Jan 26, 2005

New York, NY - Smoking was the first environmental factor clearly associated with increased risk of rheumatoid arthritis (RA). The pieces of this complex puzzle are still being worked out. In addition to the well-known interaction with the shared epitope (SE) of the HLA-DR gene, smoking also may have direct proinflammatory effects on joint tissue. Smoking also induces expression of rheumatoid factor (RF) even in subjects who do not yet have RA.

The chemical constituents of tobacco smoke that mediate this effect are well absorbed. It is not unreasonable to postulate that similar biology is occurring at other sites, including joints.

Dr Andrew J Dannenberg (Weill Medical College of Cornell University, New York, NY) reports in the January 15, 2005 issue of Cancer Research that smoking increases levels of cyclooxygenase-2 (COX-2) in oral mucosa, apparently due to increased epidermal growth factor (EGFR) signaling [ 1 ]. Dannenberg tells rheuma wire that a similar smoking-induced upregulation of COX-2 might also occur in the joints.

"Direct exposure to smoke should not be required," Dannenberg says. "The chemical constituents of tobacco smoke that mediate this effect are well absorbed. It is not unreasonable to postulate that similar biology is occurring at other sites, including joints."

EGFR mediates the COX-2 increase in smokers

This study was part of a large body of cancer research devoted to the quest for treatments to protect against or slow the development of smoking-related cancers. Coxibs have a clear preventive effect in certain types of familial precancerous intestinal polyps and are under active study in colorectal cancers.

Dannenberg found that COX-2 was overexpressed in the oral mucosa of active smokers and that this was the result of upregulated EGFR tyrosine kinase activity, leading to increased transcription of COX-2. In vitro studies showed that blocking EGFR tyrosine kinase also stopped the increase in COX-2.

Smoking also triggers the expression of RF. Dr Darcy S Majka (Northwestern University, Chicago, IL) reported at the 2004 American College of Rheumatology meeting that subjects who did not have RA but who had smoked for 20 pack-years or more were 5.75 times more likely to be RF-positive than never-smokers [ 2 ]. Those who had smoked less than 10 pack-years or 10 to 19 pack-years were not at significantly increased risk for RF positivity.

"These data suggest that heavy cigarette smoking may be a risk factor for RF seropositivity in individuals without RA. Previous data have shown that smoking is a risk factor for seropositive RA development. Because RF seropositivity often precedes clinical RA onset, the association between smoking and RA development may be mediated through mechanisms contributing to the production of RF before the onset of RA-related symptoms," Majka said.


  1. Moraitis D, Du B, De Lorenzo MS, et al. Levels of cyclooxygenase-2 are increased in the oral mucosa of smokers: Evidence for the role of epidermal growth factor receptor and its ligands. Cancer Research 2005; 65:664-670.

  2. Majka DS, Parrish LA, Ferucci ED, et al. Cigarette smoking is associated with rheumatoid factor seropositivity in a population without rheumatoid arthritis. American College of Rheumatology meeting; San Antonio, TX; Oct 16-21, 2004; Abstract 864.



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