Smoking and the risk of rheumatoid arthritis: Genes, gender, and the latest data
How strong is the evidence that smoking is a risk factor for rheumatoid arthritis?
In epidemiologic studies, cigarette smoking is strongly associated with the development of rheumatoid arthritis (RA), in particular seropositive RA. In 1987, Vessey and colleagues1 first reported an unexpectedly elevated risk of RA among women smokers in the Oxford Family Planning Association contraceptive study.
Since then, 11 case-control and 4 cohort studies have confirmed the increased risk of incident RA associated with cigarette smoking.1-16 In these studies, it appears that the risk is higher in men (odds ratio [OR] range, 1.9 to 4.4 in 6 case-control studies2,5,6,10,12,15) than in women (OR range, 0.6 to 2.5 in 8 case-control studies1,3-6,8,9,12 and 3 cohort studies11,13,16). Among RA patients with first-degree relatives who have RA, the age at onset is younger in smokers than in nonsmokers.17
Smoking intensity (number of cigarettes smoked per day) and duration are both powerful predictors of RA risk, although duration may be more important.11 The risk of incident RA is elevated for current and former smokers and remains elevated for up to 20 years after smoking cessation.13,16
Cigarette smoking primarily increases the risk of seropositive (rheumatoid factor [RF]-positive and anti-cyclic citrullinated peptide [anti-CCP] antibody-positive) RA. An interesting gene-environment interaction exists between cigarette smoking and the HLA-DRB1 shared epitope. A group of HLA-DRB1 alleles strongly associated with susceptibility to RA share a region of sequence similarity--or shared epitope--at amino acid positions 70 to 74 in the third hypervariable region of the HLA-DRB1 molecule.6,14,18 In the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) cohort study in Sweden, current smokers with 2 copies of the shared epitope had a 16-fold increased risk of RF-positive RA (95% confidence interval [CI], 7.2 to 34.2)6 and a 21-fold increased risk of anti-CCP antibody- positive RA (95% CI, 11.0 to 40.2).14
The EIRA group has proposed a new and elegant model for the pathogenesis of anti-CCP antibody-positive RA.14 Cigarette smoking may promote citrullination (the conversion of an arginine to a citrulline residue in certain peptides), and the generation of antibodies to citrullinated proteins (anti-CCP antibodies) may then occur preferentially in persons who have the shared epitope genotypes.14,19
1. Vessey MP, Villard-Mackintosh L, Yeates D. Oral contraceptives, cigarette smoking and other factors in relation to arthritis. Contraception. 1987;35:457-464.
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6. Padyukov L, Silva C, Stolt P, et al. A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheum. 2004;50:3085-3092.
7. Hutchinson D, Shepstone L, Moots R, et al. Heavy cigarette smoking is strongly associated with rheumatoid arthritis (RA), particularly in patients without a family history of RA. Ann Rheum Dis. 2001;60:223-227.
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12. Krishnan E, Sokka T, Hannonen P. Smoking-gender interaction and risk for rheumatoid arthritis. Arthritis Res Ther. 2003;5:R158-R162.
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14. Klareskog L, Stolt P, Lundberg K, et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2006;54:38-46.
15. Reckner Olsson A, Skogh T, Wingren G. Comorbidity and lifestyle, reproductive factors, and environmental exposures associated with rheumatoid arthritis. Ann Rheum Dis. 2001;60:934-939.
16. Costenbader KH, Feskanich D, Mandl LA, Karlson EW. Smoking intensity, duration, and cessation, and the risk of rheumatoid arthritis in women. Am J Med. 2006; 119:503-511.
17. Hutchinson D, Lynch MP, Moots RJ, et al. The influence of current cigarette smoking on the age of onset of rheumatoid arthritis (RA) in individuals with sporadic and familial RA. Rheumatology (Oxford). 2001;40:1068-1070.
18. Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 1987;30:1205-1213.
19. Hill JA, Southwood S, Sette A, et al. Cutting edge: the conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRB1*0401 MHC class II molecule. J Immunol. 2003;171:538-541.