Cigarette smoking has been implicated in the development of rheumatoid arthritis (RA), a systemic inflammatory disease characterized by persistent synovitis, sustained inflammation of the synovium, and progressive joint destruction.1 The association of smoking and RA development has been demonstrated through epidemiologic studies and in vivo and animal models of RA.1 

A meta-analysis reported a 40% increased risk for RA among smokers compared with never smokers, particularly among men with positive rheumatoid factor (RF) and those who are heavy smokers, although light smokers with overall low lifelong exposure of <10 pack-years also had increased risk for the development of RA.2,3

The precise pathophysiologic effects of smoking on RA remain unclear; however, several mechanisms have been proposed. Components of cigarette smoke have been shown to affect synovial inflammation, with reversal of the effect when smoking ceases.4 In addition, RA remission rates have been reported to be lower in smokers compared with nonsmokers.4

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Cigarette smoke condensate has also been shown to induce the production of proinflammatory cytokines in synovial fibroblasts, including interleukin (IL)-1α, IL-1β, IL-6, and IL-8, and in tumor necrosis factor (TNF)-α in fibroblast-like synoviocytes affected by RA. Among these, IL-1 and TNF-α are strongly associated with RA pathogenesis.5-7 These cytokines associated with smoking are thought to have several effects on the body, including on the immune system, causing oxidative stress, apoptosis, inflammation, development of autoantibodies, and epigenetic changes.1

Extraarticular manifestations of RA exacerbated by smoking include rheumatoid nodules, rheumatoid vasculitis, polyneuropathy, pleuritis, interstitial lung disease with fibrosis, pericarditis, hematologic abnormalities, ocular inflammation, secondary Sjögren syndrome, spinal disc disease, and cardiovascular disease (CVD).1 The risk for premature death from CVD has been reported to be increased by as much as 48% among those with RA who smoke cigarettes compared with the general population.3,8,9

Specific genetic factors increase the risk for RA in those who smoke. The presence of the human leukocyte antigen (HLA)-DRB1 shared epitope-containing alleles combined with smoking is associated with increased susceptibility to RA regardless of cyclic citrullinated peptide (CCP) antibody or RF status. The combination shows stronger effects in those who are anti-CCP positive/RF positive than in those who are anti-CCP negative/RF negative.10,11

Another study estimated that smoking was responsible for 35% of RA in anti-CCP-positive individuals, and that in those with the HLA-DRB1 shared epitope genotype, smoking was associated in a dose-dependent manner with increased risk for RA. In individuals carrying 2 copies of the HLA-DRB1 shared epitope, 55% of RA was attributable to smoking in anti-CCP-positive individuals.12 

There also appears to be racial preference for this susceptibility. For example, among blacks who smoke, increased risk for RA is associated with both autoantibody-positive and autoantibody-negative disease. Among whites who smoke, increased risk for RA is predominantly seen in autoantibody-positive disease. Furthermore, in blacks, the risk for RA is increased by more than fourfold in the presence of shared epitope alleles.13