Cigarette smoking and risk of rheumatoid arthritis: a dose-response meta-analysis
© Di Giuseppe et al.; licensee BioMed Central Ltd. 2014
Received: 11 November 2013
Accepted: 10 February 2014
Published: 5 March 2014
Although previous studies found that cigarette smoking is associated with risk of rheumatoid arthritis (RA), the dose-response relationship remains unclear. This meta-analysis quantitatively summarizes accumulated evidence regarding the association of lifelong exposure to cigarette smoking assessed as pack-years with the risk of RA.
Relevant studies were identified by a search of MEDLINE and EMBASE from 1966 to October 2013, with no restrictions. Reference lists from retrieved articles were also reviewed. Studies that reported relative risks (RR) or odds ratio (OR) estimates with 95% confidence intervals (CIs) for the association between pack-years of cigarette smoking and rheumatoid arthritis were included in a dose-response random-effects meta-regression analysis.
We included 3 prospective cohorts and 7 case-control studies in the meta-analysis. They included a total of 4,552 RA cases. There was no indication of heterogeneity (P heterogeneity = 0.32) and publication bias did not affect the results. Compared to never smokers, the risk of developing RA increased by 26% (RR = 1.26, 95% CI 1.14 to 1.39) among those who smoked 1 to 10 pack-years and doubled among those with more than 20 pack-years (RR for 21 to 30 pack years = 1.94, 95% CI 1.65 to 2.27). The risk of RA was not increasing further for higher exposure levels (RR for >40 pack-years = 2.07, 95% CI 1.15 to 3.73). The risk of RA was statistically significantly higher among rheumatoid factor (RF)-positive RA cases (RR = 2.47, 95% CI 2.02 to 3.02) compared to RF-negative (RR = 1.58, 95% CI 1.15 to 2.18) when comparing the highest versus lowest category of pack-years for the individual studies.
Lifelong cigarette smoking was positively associated with the risk of RA even among smokers with a low lifelong exposure. The risk of RA did not further increase with an exposure higher than 20 pack-years.
Cigarette smoking is considered an established risk factor for the development of rheumatoid arthritis (RA), an autoimmune inflammatory disease. This was confirmed by a published meta-analysis on smoking and risk of RA that showed a 40% higher risk among ever smokers compared to never smokers . However, little is known regarding the dose-response relationship between quantity of cigarette smoking and increase in the risk of RA. Previous epidemiological studies showed an increasing RA risk associated with increasing cigarette smoking [2–4], while a recently published study reported that even light smoking was associated with an increased risk of RA . Light smoking as well as heavy smoking could increase the risk of RA due to the triggering of the immune system against citrullinated proteins antigens .
The aim of the present study was to quantitatively summarize the accumulated evidence on the relation between lifelong exposure to cigarette smoking and risk of developing rheumatoid arthritis by performing a dose-response meta-analysis. As a measure of lifelong exposure we used pack-years of smoking.
We searched MEDLINE and EMBASE databases for relevant studies published from 1966 through October 2013 using the search terms “rheumatoid arthritis” or “RA” combined with “smoke”, “smoking”, “cigarette smoking” or “pack-years”, with no restrictions. Studies were excluded if they did not meet the selection criteria: use of an observational design (cohort or case-control design), examination of smoking as the main exposure and RA as the main outcome, reporting relative risks or odds ratios of RA for categories of pack-years (obtained by multiplying the number of cigarettes smoked per day by the number of years the person has smoked, divided by 20). In case of multiple publications from the same study, we selected the publication with estimates on the entire study cohort [2, 4], instead of the publications focusing only on interactions  or anticitrullinated protein antibody (ACPA) positive RA cases .
Characteristics of studies on rheumatoid arthritis and pack-years
Study population, country, follow-up period/study period
Cases/cohort size or controls
Range of exposure pack-years
RR/OR* Highest vs. lowest category§(95% CI)
Criswell et al., 2002 
Iowa Women’s Health Study, USA, 1986 to 1997
0 to 50a
Total 1.7 (1.0 to 3.0)
Age, body mass index, alcohol use, coffee consumption, marital status, occupation, age at menopause, use of oral contraceptives and hormone replacement therapy.
Costenbader et al., 2006 
Nurses’ Health Study, USA, 1976 to 2002
0 to 45a
Total 1.86 (1.46 to 2.38) RF +* 2.22 (1.63 to 3.02) RF-* 1.43 (0.96 to 2.12)
Age, body mass index, alcohol intake, father’s occupation, age at menarche, menstrual regularity, duration of breastfeeding, postmenopausal hormone use.
Di Giuseppe et al., 2013 
Swedish mammography cohort, 2003 to 2010
0 to 28b
Total 1.82 (1.19 to 2.79)
Age, menopause status, parity, alcohol use, educational level, and body mass index.
Voigt et al., 1994 
Population-based controls, USA, 1986 to 1991
Total 1.49 (1.06 to 2.10)
Age, body mass index.
Hutchinson et al., 2001 
Hospital-based controls, UK
Men + Women 239/239
0 to 55a
Total 8.41 (2.45 to 28.84)
Matched for age, gender and social class.
Olsson et al., 2001 
Population-based controls, Sweden, 1980 to 1995
Men 91/203 Women 154/222
0 to 27a
Total men 2.7 (1.2 to 5.8) Total Women 1.8 (0.7 to 4.6) RF + Men 3.4 (1.5 to 8.4) RF + Women 2.5 (0.9 to 6.7)
Age, economic status.
Stolt et al., 2003 
Population-based controls, Sweden, 1996 to 2000
Men + Women 486/724
0 to 25a
RF + 2.7 (1.8 to 3..9)
Age, residential area and gender.
Pedersen et al., 2006 
Population-based controls, Denmark, 1988 to 2003
Men 149/291 Women 366/478
0 to 25a
Total men 2.00 (1.12 to 3.58) Total Women 2.07 (1.35 to 3.16)
Birth year, year of RA diagnosis, gender.
Mikuls et al., 2010 
Population-based controls, US (African Americans)
Men + Women 605/255
0 to 15a
Total 2.37 (1.56 to 3.60) RF + 2.51 (1.63 to 3.87) RF- 1.93 (1.11 to 3.35)
Yahya et al., 2012 
Population-based controls, Malaysia, 2005 to 2009
Men + Women 1056/1416
0 to 25a
Total 2.3 (1.0 to 5.5)
Matched for age, gender and residential area. Additionally adjusted for formal education and ethnicity.
The study quality was assessed using the Newcastle-Ottawa Quality Assessment Scale (NOQAS) for cohort and case-control studies, with which each study was judged based on the selection of the study groups, the comparability of the groups, and the ascertainment of exposure and outcome . The score ranged between 0 (as poor) and 9 (as excellent). The present work follows the recommendations of the PRISMA Statement .
We conducted a two-stage dose-response random-effects meta-regression analysis [11, 12], and we estimated the dose-response relationship curve by taking into account the covariance among risk estimates for different exposure categories . The possible non-linear relationship between pack-years of smoking and risk of RA was modeled using restricted cubic splines (with three knots). This method requires stating the distribution of cases and non-cases or person-time and the relative risk (RR) or the odds ratio (OR) with its confidence intervals for at least three quantitative exposure categories. For this reason, a study that reported only two exposure categories was excluded from this meta-analysis . For another study that did not provide the distribution of cases and non-cases for each exposure level , we used the method proposed by Hamling et al.  to calculate the pseudo-counts to be able to estimate the covariance of the published ORs. For a study that reported only results stratified by menopausal status , we combined the two stratum-specific ORs using inverse variance weighted averages . The midpoint of each exposure category was assigned to each corresponding risk estimate. We assigned the midpoint of the upper open-ended category assuming that they had the same amplitude as the preceding categories, except for one study , which reported the median value of the highest category. We assigned a null value to the lowest category, composed in all the studies by never smokers. By testing if the second parameter of the restricted cubic spline model was equal to 0, we observed a limited evidence of a non-linear relationship between pack-years of smoking and RA (P = 0.078). However, the restricted cubic spline model resulted in the best fitting model in terms of the Akaike Information Criterion (AIC) when comparing it against a linear model (AICsplines = -70.0; AIClinear = -57.4).
We additionally performed a random-effects meta-analysis comparing the highest versus the lowest category of pack-years within each specific study. For this analysis the approach developed by DerSimonian and Laird was used . We conducted a sensitivity analysis in which one study at a time was removed in order to evaluate the influence of each study on the overall estimate. We also performed analyses stratified by study design (cohort, case-control), gender and rheumatoid factor (RF) type (positive, negative).
In all meta-regression models, statistical heterogeneity between studies was evaluated with the Cochran’s Q-test and the I2 statistic , which assess the proportion of total variation due to between-study variation. Publication bias was investigated by Egger’s regression asymmetry test . All reported P-values are two-sided. All statistical analyses were carried out with Stata, version 12.1 (StataCorp, College Station, TX).
Relative risks (RRs) and 95% confidence intervals (95% CIs) for categories of pack-years of smoking
RR (95% CI)
1 to 10
1.26 (1.14 to 1.39)
11 to 20
1.70 (1.44 to 2.01)
21 to 30
1.94 (1.65 to 2.27)
31 to 40
2.02 (1.44 to 2.82)
2.07 (1.15 to 3.73)
The comparison of the highest vs. the lowest categories of pack-years of smoking from the individual studies was in line with the results from the dose-response analysis showing a two-fold increase of RA risk (overall RR = 2.02, 95% CI 1.75 to 2.33). A sensitivity analysis excluding one study at a time showed that the overall RRs ranged between 1.92 and 2.10. Q test for heterogeneity of the results between specific studies was not statistically significant (Q = 12.61, P heterogeneity = 0.32). There was no evidence of publication bias (P-value from the Egger’s regression asymmetry test was 0.10).
The findings from this dose-response meta-analysis showed some evidence of a non-linear association between lifelong cigarette smoking and RA. The association was statistically significant even among those smoking less than 10 pack-years. For more than 20 pack-years the risk of RA was two-fold compared to never smokers and it stabilized with no further increase for higher levels. The risk among RF-positive RA cases was statistically significantly higher than the risk among those RF-negative.
The dose-response meta-analysis was based on a limited number of studies. Only 10 studies satisfied the inclusion criteria, of which only 3 were prospective cohort studies. In the analyses we did not observe evidence of heterogeneity. Publication bias did not affect the findings of this meta-analysis. Results from this meta-analysis are in line with the results from the previous meta-analysis , showing an increased RA risk associated with cigarette smoking. However, this meta-analysis of the dose-response relationship between cigarette smoking and RA can allow a better understanding of the association.
Among the limitations of the present study, we have to consider the limited number of studies addressing the dose-response association between lifelong exposure to cigarette smoking and RA. Moreover, a meta-analysis is influenced by the quality of the summarized studies. The quality scale used in this manuscript indicates a moderate quality for all the studies. However, this quality scale does not take into account the differences between case-control and prospective cohort design, such as different biases (for example, case-control studies may be affected by recall bias, while prospective cohort are not). Moreover, the pooled estimate from this meta-analysis could have been affected by a potential residual confounding from each study. In particular, the numbers of confounders taken into account by the case-control studies included in this meta-analysis were in general limited. This could explain the difference between the pooled OR from case-control studies and the pooled RR from prospective cohort studies. Moreover, this difference could also be explained by the different study populations: prospective cohort studies analyzed only women while all case-control studies except one  included both men and women.
The biological effect of smoking in the development of rheumatoid arthritis is still unclear. However, it is known that certain cigarette smoke components, such as nicotine, hydrocarbons and carbon monoxide, may enhance immune reactions, and it has been found that in certain inbred strains of rodents these components cause arthritis without contributions from other agents [25–27]. Moreover, it has been hypothesized that smoking interacts with HLA-DR SE genes in triggering and persuading immunity against citrullinated proteins, and that this immunity is specific for RA [6, 28]. The observed non-linear shape of the dose-response association in this meta-analysis is compatible with this triggering mechanism. RF-positive RA is more likely to be associated with the HLA-DR4 shared epitope  than RF-negative RA. This can explain the difference in risk between RF-positive and RF-negative RA cases observed in the meta-analysis.
Our study showed some evidence of a non-linear dose-response relationship between lifelong smoking and risk of RA. The risk increased at a relatively low level of lifelong exposure to smoking (≤10 pack/years) and stabilized to approximately a double risk for a smoking exposure higher than 20 pack-years.
anticitrullinated protein antibody
Akaike Information Criterion
Newcastle-Ottawa Quality Assessment Scale
This work was supported by research grants from the Swedish Research Council/Committee for Medicine, from the Swedish Research Council/Committee for Research Infrastructure for maintenance of the Swedish Mammography Cohort. Ms Di Giuseppe was supported by the Karolinska Institutet’s Award for PhD students.
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