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
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
Although there is strong evidence linking cigarette smoke exposure with RA, the specific effect of smoking on radiographic progression of disease is less clear. There is some evidence that smoking may be a risk factor for radiographic progression in early RA.14,15 It is unknown, however, the extent to which smoking cessation can halt progression or reverse pathologic changes associated with RA.
Data from the Consortium of Rheumatology Researchers of North America and from the Better Anti‐Rheumatic PharmacOTherapy (BARFOT) project in early RA in Sweden showed that smoking cessation after the onset of RA did not change the prognosis for smokers with RA.16,17 In fact, it has been reported that the risk for RA may persist for several years after smoking cessation, even among moderate smokers.18
The discovery that cigarette smoke condensate can induce the production of proinflammatory cytokines in synovial fibroblasts has led to growing interest in how smoking affects response to RA treatment, particularly to biologic agents. The available research is conflicting. A study by Maska and colleagues reported that, among patients with early RA and poor prognostic factors, smoking status had no impact on treatment response to early combination therapy (methotrexate + etanercept or methotrexate + hydroxychloroquine + sulfasalazine triple therapy) or initial methotrexate with step-up therapy (methotrexate + etanercept) or to triple therapy .19
Another study reported by the Agency for Healthcare Research and Quality concluded that among individuals with RA of <3 years duration, smoking does not reduce the effectiveness of RA treatment.20 In heavy smokers with advanced disease, however, it appears that smoking can attenuate treatment response. For example, a review by
Change and colleagues of available studies on smoking and RA concluded that smoking aggravates RA and decreases response to TNF-α antagonist treatment. This conclusion was based on serology results, cytokine levels, and pharmacokinetic/pharmacodynamic studies,1 and is supported by a real-life cohort study in patients with axial spondyloarthritis, which also found an association between smoking and impaired response to TNF-α antagonist treatment.21
Although the rates of cigarette smoking among US adults has decreased over the past 50 years from 42.4% to 17.8%,22 rates of smoking cessation among blacks remain consistently lower compared with whites.23 The combination of negative health effects associated with smoking and its role in increasing the risk for RA in some individuals provides a compelling case for continued smoking cessation efforts.3,24
Smoking cessation is one of the most important modiﬁable lifestyle factors that can improve outcomes for those with RA. It has been shown that the risk for anti-CCP antibody-positive RA was reduced with smoking cessation,12 and therefore, counseling against smoking should be mandatory in all rheumatology practices.
Smoking cessation interventions have traditionally been designed for smokers without long-term illness. Interventions for those with speciﬁc long-term diseases such as CVD diabetes mellitus, and chronic obstructive pulmonary disease have received surprisingly little attention, and to date no RA-speciﬁc smoking cessation interventions have been published.3,25 This is reflected in the results of an international study involving 395 rheumatologists from 25 countries, which reported that advice for smoking cessation within rheumatology departments is inconsistent, and a specific protocol for smoking cessation is not consistently available. In fact, only 1 in 5 rheumatology departments had either a specific protocol or written advice for smoking cessation.26
Furthermore, disease-related issues may hinder smoking cessation efforts among those with RA. Five key barriers to smoking cessation have been identified: lack of awareness about the relationship between smoking and RA, smoking as a distraction from the pain of RA, difﬁculty exercising as an alternative distraction, smoking as a coping mechanism for RA, and lack of support in smoking cessation efforts.3,27
These findings highlight the need to improve patient awareness of the impact of smoking on RA and the importance of developing and implementing smoking cessation protocols in rheumatology practices. Providing education to patients and clearly demonstrating the link between RA and smoking may translate to decreased smoking among those with RA.28
Summary and Clinical Applicability
Smoking is a preventable modifiable risk factor for morbidity and mortality associated with RA, and therefore counseling and support for smoking cessation should be mandatory in rheumatology practices. Rheumatologists however lack specific guidance on strategies for smoking cessation, and patients face barriers, including lack of knowledge about the link between smoking and RA, which often translate to lack of motivation to stop smoking.
Strategies for rheumatologists that include guidelines tailored speciﬁcally for those with RA who smoke and that facilitate patient education, exercise, pain management, coping strategies, and support may increase smoking cessation efforts among smokers with RA.
1. Chang K, Yang SM, Kim SH, Han KH, Park SJ, Shin JI. Smoking and rheumatoid arthritis. Int J Mol Sci. 2014;15(12):22279-22295.
2. Di Giuseppe D, Discacciati A, Orsini N, Wolk A. Cigarette smoking and risk of rheumatoid arthritis: a dose-response meta-analysis. Arthritis Res Ther. 2014;16(2):R61.
3. Sugiyama D, Nishimura K, Tamaki K, et al. Impact of smoking as a risk factor for developing rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis. 2010;69(1):70-81
4. Aimer P, Stamp L, Stebbings S, Valentino N, Cameron V, Treharne GJ. Identifying barriers to smoking cessation in rheumatoid arthritis. Arthritis Care Res (Hoboken). 2015;67(5):607-615.
5. Anderson R, Meyer PW, Ally MM, Tikly M. Smoking and air pollution as pro-inflammatory triggers for the development of rheumatoid arthritis. Nicotine Tob Res. 2016 Mar 8. [Epub ahead of print]
6. Shizu M, Itoh Y, Sunahara R, et al. Cigarette smoke condensate upregulates the gene and protein expression of proinflammatory cytokines in human fibroblast-like synoviocyte line. J Interferon Cytokine Res. 2008;28(8):509-521.
7. Adachi M, Okamoto S, Chujyo S, et al. Cigarette smoke condensate extracts induce IL-1-beta production from rheumatoid arthritis patient-derived synoviocytes, but not osteoarthritis patient-derived synoviocytes, through aryl hydrocarbon receptor-dependent NF-kappa-B activation and novel NF-kappa-B sites. J Interferon Cytokine Res. 2013;33(6):297-307.
8. Joseph RM, Movahedi M, Dixon WG, Symmons DP. Smoking-related mortality in patients with early rheumatoid arthritis – a retrospective cohort study using the Clinical Practice Research Datalink. Arthritis Care Res (Hoboken). 2016 Mar 18. [Epub ahead of print]
9. Farragher TM, Goodson NJ, Naseem H, et al. Association of the HLA-DRB1 gene with premature death, particularly from cardiovascular disease, in patients with rheumatoid arthritis and inflammatory polyarthritis. Arthritis Rheum. 2008;58(2):359-369.
10. Bang SY, Lee KH, Cho SK, Lee HS, Lee KW, Bae SC. Smoking increases rheumatoid arthritis susceptibility in individuals carrying the HLA-DRB1 shared epitope, regardless of rheumatoid factor or anti-cyclic citrullinated peptide antibody status. Arthritis Rheum. 2010;62(2):369-377.
11. Klareskog L, Padyukov L, Alfredsson L. Smoking as a trigger for inflammatory rheumatic diseases. Curr Opin Rheumatol. 2007;19(1):49-54.
12. Källberg H, Ding B, Padyukov L, et al. Smoking is a major preventable risk factor for rheumatoid arthritis: estimations of risks after various exposures to cigarette smoke. Ann Rheum Dis. 2011;70(3):508-511.
13. Mikuls TR, Sayles H, Yu F, et al. Associations of cigarette smoking with rheumatoid arthritis in African Americans. Arthritis Rheum. 2010;62(12):3560-3568.
14. De Rooy DP, van Nies JA, Kapetanovic MC, et al. Smoking as a risk factor for the radiological severity of rheumatoid arthritis: a study on six cohorts. Ann Rheum Dis. 2014;73(7):1384-1387.
15. Saevarsdottir S, Rezaei H, Geborek P, et al. Current smoking status is a strong predictor of radiographic progression in early rheumatoid arthritis: results from the SWEFOT trial. Ann Rheum Dis. 2015;74(8):1509-1514.
16. Fisher MC, Hochberg MC, El-Taha M, Kremer JM, Peng C, Greenberg JD. Smoking, smoking cessation, and disease activity in a large cohort of patients with rheumatoid arthritis. J Rheumatol. 2012;39(5):904-909.
17. Andersson ML, Bergman S, Söderlin MK. The effect of stopping smoking on disease activity in rheumatoid arthritis (RA). Data from BARFOT, a multicenter study of early RA. Open Rheumatol J. 2012;6:303-309.
18. Stolt P, Bengtsson C, Nordmark B, et al. Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases. Ann Rheum Dis. 2003;62(9):835-841.
19. Maska LB, Sayles HR, O’Dell JR, et al. Serum cotinine as a biomarker of tobacco exposure and the association with treatment response in early rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64(12):1804-1810.
20. Agency for Healthcare Research and Quality. Smoking does not reduce the effectiveness of rheumatoid arthritis treatment. http://www.ahrq.gov/news/newsletters/research-activities/13jul/0713ra22.html. Published July 2013. Accessed March 26, 2016.
21. Ciurea A, Scherer A, Weber U, et al. Impaired response to treatment with tumour necrosis factor α inhibitors in smokers with axial spondyloarthritis. Ann Rheum Dis. 2016;75(3):532-539.
22. Rifkin J. Why Cigarette Usage Is At Record Lows And Dropping. http://www.huffingtonpost.com/2015/03/26/cigarette-smoking-decline_n_6855468.html. Updated March 30, 2015. Accessed March 26, 2016.
23. U.S. Department of Health and Human Services. Tobacco Use Among U.S, Racial/Ethnic Groups: African Americans, American Indians and Alaska Natives, Asian Americans and Pacific Islanders, and Hispanics. A Report of the Surgeon General 1998. http://www.cdc.gov/tobacco/data_statistics/sgr/1998/complete_report/pdfs/complete_report.pdf. Published 1998. Accessed March 26, 2016.
24. Centers for Disease Control and Prevention. Health Effects of Cigarette Smoking. http://www.cdc.gov/tobacco/data_statistics/fact_sheets/health_effects/effects_cig_smoking/. Updated October 1, 2015. Accessed March 26, 2016.
25. Gritz ER, Vidrine DJ, Fingeret MC. Smoking cessation a critical component of medical management in chronic disease populations. Am J Prev Med. 2007;33(6 Suppl): S414-S422.
26. Naranjo A, Khan NA, Cutolo M, et al. Smoking cessation advice by rheumatologists: results of an international survey. Rheumatology (Oxford). 2014;53(10):1825-1829.
27. Stamp LK, Gath M, Aimer P, Stebbings S, Treharne G. Promoting Smoking Cessation Among Rheumatoid Arthritis Patients: What Motivations and Barriers Are Reported after Being Offered a Smoking Cessation Intervention? Arthritis Rheumatol. 2015;67 (suppl 10):1489. https://acrabstracts.org/abstract/promoting-smoking-cessation-among-rheumatoid-arthritis-patients-what-motivations-and-barriers-are-reported-after-being-offered-a-smoking-cessation-intervention/. Published September 29, 2015. Accessed March 26, 2016.
28. Harris HE, Tweedie F, White M, Samson K. How to motivate patients with rheumatoid arthritis to quit smoking. J Rheumatol. 2016 Feb 15. [Epub ahead of print]