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Cigarette smoking, alcohol consumption and risk of systemic lupus erythematosus SU Takvorian, JF Merola and KH Costenbader Lupus 2014 23: 537 DOI: 10.1177/0961203313501400 The online version of this article can be found at: http://lup.sagepub.com/content/23/6/537
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Lupus (2014) 23, 537–544 http://lup.sagepub.com
SPECIAL ARTICLE
Cigarette smoking, alcohol consumption and risk of systemic lupus erythematosus SU Takvorian1, JF Merola2 and KH Costenbader1,3 1
Department of Medicine; 2Department of Dermatology; and 3Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disease whose pathogenesis is thought to involve both genetic and environmental factors. It is possible that common environmental exposures, such as cigarette smoking and alcohol consumption, might modify risk of disease development in certain individuals. Here we aim to review the epidemiologic evidence related to the association of cigarette smoking, alcohol consumption and the risk of developing SLE. A growing body of evidence suggests that cigarette smoking confers a short-term increased risk of SLE in genetically susceptible individuals. On the other hand, alcohol consumption in moderate doses may have a protective effect against the development of SLE, although this is still debated. We also have reviewed proposed mechanistic explanations underlying the role of cigarette smoking and alcohol consumption in SLE pathogenesis. Lupus (2014) 23, 537–544. Key words: Systemic lupus erythematosus; risk factors; environmental exposure
Introduction Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disease whose pathogenesis remains incompletely understood. The current paradigm is that environmental exposures trigger the development of disease and disease phenotype in genetically susceptible individuals.1 Twin concordance studies, commonly used to quantify the role of gene inheritance in disease susceptibility, suggest an important role for environmental as well as genetic factors in SLE susceptibility, with concordance rates between monozygotic twins ranging from 11% to 57%.2 Although SLE is a rare disease, it is possible that exposures linked to its susceptibility could be quite common, related to dose and duration of exposure or specific gene-environment interactions. Two such common exposures that have been studied in several epidemiologic studies are cigarette smoking and alcohol consumption. Cigarette smoking has consistently been found to be strongly associated
Correspondence to: Samuel Takvorian, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA. Email: [email protected]
with the development of rheumatoid arthritis (RA), but its role in the pathogenesis of SLE is less well understood.3,4 Alcohol consumption, a habit that often accompanies smoking, may protect against the development of SLE, although this is still debated.5 The purpose of this article is to review the existing literature pertaining to the association of cigarette smoking, alcohol consumption and the risk of developing SLE. We also aim to explore potential mechanisms by which these environmental factors might be involved in the pathogenesis of SLE.
Methods We performed a comprehensive literature search on PubMed for all years available through February 2013, using the following search terms: ‘‘smoking,’’ ‘‘cigarette,’’ ‘‘alcohol’’ and ‘‘risk factor,’’ each matched with ‘‘systemic lupus.’’ We restricted our search to studies of humans, published in English. This generated 924 results, of which 224 pertained to smoking as a risk factor and 78 pertained to alcohol as a risk factor. We excluded case reports and case series from our analysis, as well as reviews,
! The Author(s), 2013. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
Downloaded from lup.sagepub.com at PORTLAND STATE UNIV on September 13, 2014
10.1177/0961203313501400
Cigarette smoking, alcohol consumption and risk of SLE SU Takvorian et al.
538
1105 articles identified through PubMed database search
1105 articles screened
419 excluded (non-English, animal studies, case reports, reviews)
686 titles/abstracts screened
662 excluded (basic science, not smoking or alcohol, not SLE)
27 articles included in final analysis (including 3 additional articles identified through Web of Science search)
Figure 1
Flow Diagram of Literature Search Strategy.
editorials and studies not related to cigarette smoking or alcohol consumption and SLE. We cross-referenced our search using Web of Science to ensure that appropriate citations were reviewed. Ultimately, we included 27 studies in our analysis: 14 case-control studies, 11 cohort studies and two meta-analyses (Figure 1).
Cigarette smoking Epidemiology Several,6–10 but not all,11–16 epidemiologic studies have reported an increased risk of SLE among smokers. In many of these studies, which were performed in a wide variety of geographic locations and employed a range of hospital and populationbased controls, current smoking was a stronger risk factor than former smoking.6,9,10 Two of these studies showed a dose-response relationship, wherein higher daily or cumulative exposure to cigarette smoke was associated with a higher risk of SLE.6,9 Three other studies were unable to find a dose effect,8,10,13 and the others did not investigate a dose effect. A 2004 meta-analysis of seven case-control studies and two cohort studies found that current smokers, but not former smokers, had a modestly
increased risk of SLE compared to nonsmokers (odds ratio (OR) 1.50, 95% confidence interval (CI) 1.09–2.08)17 (Figure 2). The case-control studies included were a heterogeneous group with varying definitions of smoking status, questionnaire response rates, adjustment for potential confounders and timing of the study questionnaire in relation to the onset of SLE. Most strikingly, the results of the study by Ghaussy et al.,8 which was performed in New Mexico in a predominantly Hispanic population and used general medical outpatients as controls, were remarkably higher than those of the rest of the studies: an OR of 6.7 for current smokers and 3.7 for former smokers, whereas the remainder of the studies reported ORs ranging from 0.9 to 2.3 for current smokers and 0.6 to 1.2 for former smokers. An accompanying sensitivity analysis in which this outlying study was excluded showed that it did have a large influence on the summary effect and was responsible for much of the statistical heterogeneity observed between studies. Nevertheless, when excluding this study, the OR for current smoking was still elevated at 1.31 (95% CI 1.02–1.70). Taken together, these results suggest that smoking status may confer an immediate risk for SLE, and that, with time after the cessation of smoking, the risk of SLE returns to that observed in those who have never smoked.
Lupus Downloaded from lup.sagepub.com at PORTLAND STATE UNIV on September 13, 2014
Cigarette smoking, alcohol consumption and risk of SLE SU Takvorian et al.
539
(A)
(B)
Figure 2 Forest Plot of Odds Ratios (ORs) of SLE developing in (A) current smokers versus never smokers and (B) former smokers versus never smokers, including meta-analysis summary estimates (diamonds). Reproduced with permission from: Costenbader KH, Kim DJ, Peerzada J, Lockman S, Nobles-Knight D, Petri M, et al. Cigarette smoking and the risk of systemic lupus erythematosus: A meta-analysis. Arthritis Rheum 2004;50:849-57.17
Since then, two case-control studies have been performed in Japan. Washio et al. investigated the impact of smoking and other lifestyle factors on the risk of SLE among women residing in two regions of Japan.7 Compared to never smokers, those who had ever smoked (current and former smokers) were at significantly increased risk of SLE after adjusting for age in both regions (OR 2.24, 95% CI 1.29–3.88 in Kyushu; OR 2.41, 95% CI 1.01–5.74 in Hokkaido). A second case-control study from the same two regions in Japan included more cases from each region and reported that current smokers were at significantly increased risk of SLE compared with nonsmokers (OR 3.06, 95% CI 1.86–5.03), after adjustment for age, region, alcohol consumption and educational background.6 Investigators also found a dose-response relationship between average number of cigarettes smoked per day, cigarette-years of smoking, fraction smoked per cigarette and degree of smoke inhalation and SLE risk (all p for trends 150 g/month was compared with none, and subjects’ alcohol consumption was defined as the maximum monthly consumption before SLE (or index date for controls). In this study, alcohol consumption was strongly protective against SLE (ORadj 0.2, 95% CI 0.1–0.5).12 In Japan, a case-control study involving 171 SLE cases and 492 unmatched controls found that light/ moderate alcohol consumption was inversely associated with SLE risk, irrespective of type of alcoholic beverage consumed.6 These findings clarified an earlier analysis by Washio et al. from the same population, which produced conflicting results.7 Investigators initially found a dose-response effect in the Kyushu region, wherein higher-frequency drinkers were at increased odds of developing SLE, but this association was not seen in the Hokkaido region. When investigators reanalyzed the association in their later study,6 using nondrinkers as a reference category instead of subjects who drank
http://lup.sagepub.com/
Cigarette smoking, alcohol consumption and risk of systemic lupus erythematosus SU Takvorian, JF Merola and KH Costenbader Lupus 2014 23: 537 DOI: 10.1177/0961203313501400 The online version of this article can be found at: http://lup.sagepub.com/content/23/6/537
Published by: http://www.sagepublications.com
Additional services and information for Lupus can be found at: Email Alerts: http://lup.sagepub.com/cgi/alerts Subscriptions: http://lup.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> Version of Record - Apr 24, 2014 What is This?
Downloaded from lup.sagepub.com at PORTLAND STATE UNIV on September 13, 2014
Lupus (2014) 23, 537–544 http://lup.sagepub.com
SPECIAL ARTICLE
Cigarette smoking, alcohol consumption and risk of systemic lupus erythematosus SU Takvorian1, JF Merola2 and KH Costenbader1,3 1
Department of Medicine; 2Department of Dermatology; and 3Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disease whose pathogenesis is thought to involve both genetic and environmental factors. It is possible that common environmental exposures, such as cigarette smoking and alcohol consumption, might modify risk of disease development in certain individuals. Here we aim to review the epidemiologic evidence related to the association of cigarette smoking, alcohol consumption and the risk of developing SLE. A growing body of evidence suggests that cigarette smoking confers a short-term increased risk of SLE in genetically susceptible individuals. On the other hand, alcohol consumption in moderate doses may have a protective effect against the development of SLE, although this is still debated. We also have reviewed proposed mechanistic explanations underlying the role of cigarette smoking and alcohol consumption in SLE pathogenesis. Lupus (2014) 23, 537–544. Key words: Systemic lupus erythematosus; risk factors; environmental exposure
Introduction Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disease whose pathogenesis remains incompletely understood. The current paradigm is that environmental exposures trigger the development of disease and disease phenotype in genetically susceptible individuals.1 Twin concordance studies, commonly used to quantify the role of gene inheritance in disease susceptibility, suggest an important role for environmental as well as genetic factors in SLE susceptibility, with concordance rates between monozygotic twins ranging from 11% to 57%.2 Although SLE is a rare disease, it is possible that exposures linked to its susceptibility could be quite common, related to dose and duration of exposure or specific gene-environment interactions. Two such common exposures that have been studied in several epidemiologic studies are cigarette smoking and alcohol consumption. Cigarette smoking has consistently been found to be strongly associated
Correspondence to: Samuel Takvorian, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA. Email: [email protected]
with the development of rheumatoid arthritis (RA), but its role in the pathogenesis of SLE is less well understood.3,4 Alcohol consumption, a habit that often accompanies smoking, may protect against the development of SLE, although this is still debated.5 The purpose of this article is to review the existing literature pertaining to the association of cigarette smoking, alcohol consumption and the risk of developing SLE. We also aim to explore potential mechanisms by which these environmental factors might be involved in the pathogenesis of SLE.
Methods We performed a comprehensive literature search on PubMed for all years available through February 2013, using the following search terms: ‘‘smoking,’’ ‘‘cigarette,’’ ‘‘alcohol’’ and ‘‘risk factor,’’ each matched with ‘‘systemic lupus.’’ We restricted our search to studies of humans, published in English. This generated 924 results, of which 224 pertained to smoking as a risk factor and 78 pertained to alcohol as a risk factor. We excluded case reports and case series from our analysis, as well as reviews,
! The Author(s), 2013. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
Downloaded from lup.sagepub.com at PORTLAND STATE UNIV on September 13, 2014
10.1177/0961203313501400
Cigarette smoking, alcohol consumption and risk of SLE SU Takvorian et al.
538
1105 articles identified through PubMed database search
1105 articles screened
419 excluded (non-English, animal studies, case reports, reviews)
686 titles/abstracts screened
662 excluded (basic science, not smoking or alcohol, not SLE)
27 articles included in final analysis (including 3 additional articles identified through Web of Science search)
Figure 1
Flow Diagram of Literature Search Strategy.
editorials and studies not related to cigarette smoking or alcohol consumption and SLE. We cross-referenced our search using Web of Science to ensure that appropriate citations were reviewed. Ultimately, we included 27 studies in our analysis: 14 case-control studies, 11 cohort studies and two meta-analyses (Figure 1).
Cigarette smoking Epidemiology Several,6–10 but not all,11–16 epidemiologic studies have reported an increased risk of SLE among smokers. In many of these studies, which were performed in a wide variety of geographic locations and employed a range of hospital and populationbased controls, current smoking was a stronger risk factor than former smoking.6,9,10 Two of these studies showed a dose-response relationship, wherein higher daily or cumulative exposure to cigarette smoke was associated with a higher risk of SLE.6,9 Three other studies were unable to find a dose effect,8,10,13 and the others did not investigate a dose effect. A 2004 meta-analysis of seven case-control studies and two cohort studies found that current smokers, but not former smokers, had a modestly
increased risk of SLE compared to nonsmokers (odds ratio (OR) 1.50, 95% confidence interval (CI) 1.09–2.08)17 (Figure 2). The case-control studies included were a heterogeneous group with varying definitions of smoking status, questionnaire response rates, adjustment for potential confounders and timing of the study questionnaire in relation to the onset of SLE. Most strikingly, the results of the study by Ghaussy et al.,8 which was performed in New Mexico in a predominantly Hispanic population and used general medical outpatients as controls, were remarkably higher than those of the rest of the studies: an OR of 6.7 for current smokers and 3.7 for former smokers, whereas the remainder of the studies reported ORs ranging from 0.9 to 2.3 for current smokers and 0.6 to 1.2 for former smokers. An accompanying sensitivity analysis in which this outlying study was excluded showed that it did have a large influence on the summary effect and was responsible for much of the statistical heterogeneity observed between studies. Nevertheless, when excluding this study, the OR for current smoking was still elevated at 1.31 (95% CI 1.02–1.70). Taken together, these results suggest that smoking status may confer an immediate risk for SLE, and that, with time after the cessation of smoking, the risk of SLE returns to that observed in those who have never smoked.
Lupus Downloaded from lup.sagepub.com at PORTLAND STATE UNIV on September 13, 2014
Cigarette smoking, alcohol consumption and risk of SLE SU Takvorian et al.
539
(A)
(B)
Figure 2 Forest Plot of Odds Ratios (ORs) of SLE developing in (A) current smokers versus never smokers and (B) former smokers versus never smokers, including meta-analysis summary estimates (diamonds). Reproduced with permission from: Costenbader KH, Kim DJ, Peerzada J, Lockman S, Nobles-Knight D, Petri M, et al. Cigarette smoking and the risk of systemic lupus erythematosus: A meta-analysis. Arthritis Rheum 2004;50:849-57.17
Since then, two case-control studies have been performed in Japan. Washio et al. investigated the impact of smoking and other lifestyle factors on the risk of SLE among women residing in two regions of Japan.7 Compared to never smokers, those who had ever smoked (current and former smokers) were at significantly increased risk of SLE after adjusting for age in both regions (OR 2.24, 95% CI 1.29–3.88 in Kyushu; OR 2.41, 95% CI 1.01–5.74 in Hokkaido). A second case-control study from the same two regions in Japan included more cases from each region and reported that current smokers were at significantly increased risk of SLE compared with nonsmokers (OR 3.06, 95% CI 1.86–5.03), after adjustment for age, region, alcohol consumption and educational background.6 Investigators also found a dose-response relationship between average number of cigarettes smoked per day, cigarette-years of smoking, fraction smoked per cigarette and degree of smoke inhalation and SLE risk (all p for trends 150 g/month was compared with none, and subjects’ alcohol consumption was defined as the maximum monthly consumption before SLE (or index date for controls). In this study, alcohol consumption was strongly protective against SLE (ORadj 0.2, 95% CI 0.1–0.5).12 In Japan, a case-control study involving 171 SLE cases and 492 unmatched controls found that light/ moderate alcohol consumption was inversely associated with SLE risk, irrespective of type of alcoholic beverage consumed.6 These findings clarified an earlier analysis by Washio et al. from the same population, which produced conflicting results.7 Investigators initially found a dose-response effect in the Kyushu region, wherein higher-frequency drinkers were at increased odds of developing SLE, but this association was not seen in the Hokkaido region. When investigators reanalyzed the association in their later study,6 using nondrinkers as a reference category instead of subjects who drank
