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STUDY

Association of Cigarette Smoking but Not Alcohol


Consumption With Cutaneous Lupus Erythematosus
Peggy Boeckler, MD; Anne Cosnes, MD; Camille Francs, MD; Guy Hedelin, PhD; Dan Lipsker, MD, PhD

Objective: To ascertain whether smoking or alcohol con-

sumption is associated with lupus erythematosus (LE),


because this topic is still subject to debate and part of
the debate could be related to the fact that smoking and
alcohol consumption are specific risk factors for cutaneous LE.
Design: Prospective multicenter case-control study.
Setting: Three French university hospitals.
Patients: One hundred eight patients with LE and 216
control subjects.
Intervention: Standardized questionnaire evaluating

cigarette smoking and alcohol consumption.


Main Outcome Measures: The statistical significance of smoking history and alcohol consumption as associated risk factors for LE by estimating matched casecontrol odds ratios and their 95% confidence intervals,
using multiple conditional logistic regression and the Breslow-Day test to investigate differences in quantities of cigarette and alcohol consumption.

Author Affiliations: Clinique


Dermatologique (Drs Boeckler
and Lipsker) and Laboratoire
dEpidemiologie et de Sante
Publique (Dr Hedelin), Faculte
de Medecine, Universite de
Strasbourg, Strasbourg, France;
Study Group of Systemic
Diseases in Dermatology
(EMSED: Etude des Maladies
Systemiques en Dermatologie),
France (Drs Boeckler, Cosnes,
Francs, and Lipsker); Service
de Dermatologie, Centre
Hospitalier Universitaire de
Creteil, Creteil, France
(Dr Cosnes); and Services de
Medecine Interne, Centre
Hospitalier Universitaire
Pitie/Tenon (Dr Francs), and
Centre Hospitalier Universitaire
Pitie/Tenon (Dr Francs),
Paris, France.

Results: Of the LE patients, 73.1% smoked compared


with 49.5% of controls, (odds ratio, 2.77; 95% confidence interval, 1.63-4.76). There was no significant difference in alcohol consumption between LE patients and
controls. Among the 79 LE patients who smoked, 72
(91.1%) had started smoking before the first manifestation of LE (mean delay between initiation of smoking and
first signs of LE, 14.1 years). The LE patients smoked significantly more than controls did (11.7 vs 7.0 packyears; P =.002). The prevalence of smoking among patients who met more than 4 American College of
Rheumatology (ACR) criteria and/or with antinuclear
DNA antibodies was lower than the prevalence in patients who met fewer than 4 ACR criteria or than the
prevalence in controls (P .001).
Conclusions: Cigarette smoking is associated with LE,
but alcohol consumption is not. The risk conferred by
cigarette smoking seems highest in patients who meet
fewer than 4 ACR criteria and/or who do not have antinuclear DNA antibodies.

Arch Dermatol. 2009;145(9):1012-1016

HE ETIOLOGY OF LUPUS ERY-

thematosus (LE) has not


yet been elucidated in detail, although genetic and
environmental factors play
a role in its development. Commonly accepted environmental etiological factors include exposure to UV light and drugs.1,2
Some epidemiological studies have suggested that smoking tobacco is a risk factor for LE, probably in genetically predisposed individuals.3-7 However, whether
cigarette smoking increases the risk of developing systemic LE (SLE) remains controversial. To date, 3 case-control studies3-5 have reported significantly increased
odds ratios (ORs) for the development of
SLE in smokers, whereas 6 others have not
found a clear association.8-13 Thus, the precise effect of cigarette smoking and/or alcohol consumption on LE is not clearly established. Most studies focused on SLE,

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and the patients included were almost exclusively women. We and other authors6,7,14 have previously shown that cigarette smoking could be specifically
involved in the pathogenesis of cutaneous LE. Thus, the effect of cigarette smoking could specifically involve a subgroup
of patients with cutaneous LE, and analysis of this effect should not be restricted
to patients who meet 4 or more American College of Rheumatology (ACR) criteria. On the other hand, alcohol consumption seems to be associated with a
decreased risk of LE.4,5 We conducted a
multicenter prospective study to evaluate cigarette smoking and alcohol consumption as risk factors for developing cutaneous LE in a large series of patients
compared with control subjects. In this report of our results, we also discuss the
physiopathological role of cigarette smoking in LE.

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METHODS

Table 1. Subtypes of LE According to the Sex

From 2004 to 2006, cases and controls were recruited from outpatients of 3 French university hospitals that are strongly involved in the care of patients with connective tissue diseases:
the Dermatology Clinic of the University of Strasbourg (center 1), the Dermatology Service of the University of Creteil (center 2), and the Internal Medicine Service of the University of
Pitie/Tenon (center 3). All consecutive patients presenting with
LE who underwent evaluation at the centers were included in
the study.

CASES AND CONTROLS


The diagnosis of discoid LE (DLE), disseminated DLE, tumid LE,
and acute LE was made according to established clinical and histopathological criteria.15 The diagnosis of subacute LE was established according to the definition of Sontheimer et al.1 The patients who fulfilled 4 or more ACR criteria were defined as having
SLE.16 Each patient was examined by a skilled practitioner involved in the care of LE patients (including A.C., C.F., and D.L.).
We recorded the type of cutaneous lesion of LE, the date of the
diagnosis of LE and of its first manifestations, the duration of the
disease, the type and the number of ACR criteria, the presence
and level of antinuclear DNA (anti-nDNA) antibodies and their
specificities, and the levels of C3 and C4. Systemic involvement
was quiescent in all patients during the preceding 6 months, and
treatment was unchanged during that period.
For each case, 2 controls matched for sex and year of birth
(5 years) were randomly selected from the relatives (mainly
husband and wife) of the cases included in the study and other
patients undergoing surgery (mainly excision of nevi).

QUESTIONNAIRE
A self-administered questionnaire was obtained from the LE
patients and from the controls. We asked the patients about
their smoking habits (the number of cigarettes smoked a day
and the patients ages when they started and stopped smoking) and their alcohol consumption (frequency, type, and quantity of alcoholic drinks consumed). Regular cigarette smoking
was defined as smoking at least 1 cigarette a day for at least 3
months. Cigarette smoking was quantified in pack-years, and
alcohol consumption was quantified in grams per year. We also
considered the time between the diagnosis of LE and the beginning of the use of tobacco and alcohol.

STATISTICAL ANALYSIS
The statistical significance of smoking history and alcohol as
associated factors for LE was analyzed by estimating matched
case-control ORs and their 95% confidence intervals (CIs) with
the use of multiple conditional logistic regression and multiple stratified logistic regression. To investigate differences in
the quantities of cigarettes smoked and alcohol consumed, the
Breslow-Day test was used.17
All patients and controls gave oral consent to participate in
the study. Under French law, a study that relies on a questionnaire only does not need approval of an ethics committee or
institutional review board.
RESULTS

We included 108 LE patients (28 male and 80 female;


female to male ratio, 3.3) and 216 controls in the study.

No. (%) of LE Patients a


Subtype
DLE
Disseminated DLE
Tumid LE
Subacute LE
Acute LE
Other b
Total

Female

Male

21 (19.4)
16 (14.8)
6 (5.6)
16 (14.8)
16 (14.8)
5 (4.6)
80

8 (7.4)
7 (6.5)
1 (0.9)
10 (9.3)
1 (0.9)
1 (0.9)
28

Abbreviations: DLE, discoid lupus erythematosus (LE).


a Percentages are based on the total number of 108 LE patients, have been
rounded, and might not total 100.
b Includes patients who met 4 or more American College of Rheumatology
criteria and who had nonspecific skin lesions.

The mean age of patients was 40.1 (range, 17-73) years.


Subtypes of LE included DLE or disseminated DLE in
48.1%, subacute LE in 24.1%, and acute LE in 15.7%
(Table 1). The remaining patients had tumid LE or SLE
with no specific cutaneous lesions (Table 1). The latter group included 6 patients with SLE who had nonspecific cutaneous lesions of LE such as pyoderma
gangrenosum, aseptic pustules, or vasculitis. Mean
duration of the disease was 7.4 years (range, 1 month
to 45 years), and the mean time from the first manifestation of LE to the diagnosis was 1.5 years (range, 1
month to 20 years).
There was a great disparity between the number of male
patients included in the different centers. Center 1 included 53 patients with a female to male ratio of 1.2,
whereas center 2 included 33 female patients and only 1
male patient (female to male ratio, 33.0), and center 3
included 21 patients with a female to male ratio of 6.0.
Table 2 shows the distribution of smoking and alcohol status among the cases and controls. Overall, significantly more of the LE patients (73.1%) were smokers compared with the controls (49.5%) (P .001) (OR,
2.77; 95% CI, 1.63-4.76). The Breslow-Day test showed
an effect of center (P .001) (Table 2). Thus, the ORs
for each center are 9.26 (95% CI, 3.65-26.5) for center
1, 1.20 (95% CI, 0.47-3.14) for center 2, and 1.00 (95%
CI, 0.31-3.26) for center 3.
There was no significant difference in alcohol consumption between LE patients and controls in the entire population or in the different centers.
Among the 79 LE patients who smoked, 72 (91.1%)
had started smoking before the first manifestation of LE
(mean delay between initiation of smoking and the first
signs of LE, 14.1 years [range, 6 months to 49 years]).
Only 2 patients were former smokers, and 7 started smoking after the diagnosis of the disease. At the time of the
study, they had smoked for a mean of 20 years (22 years
for male and 18.5 years for female patients). Mean cigarette consumption was 15 cigarettes a day (15.4 cigarettes a day for male and 14.9 cigarettes a day for female
patients).
The prevalence of smoking was higher in LE patients
than in controls of either sex (Table 3). The difference
was greater in male subjects. Male subjects smoked more

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Table 2. Prevalence of Risk Factors in LE Patients and Controls


Subgroup No./Total No. (%)
LE Patients

Controls

P Value, Test a

79/108 (73.1)
46/53 (86.8)

107/216 (49.5)
44/106 (41.5)

22/34 (64.7)
11/21 (52.4)

41/68 (60.3)
22/42 (52.4)

.001, Fisher test


.001, Fisher test and .001 (center),
Breslow-Day test
NS
NS

76/108 (70.4)

173/216 (80.1)

Risk Factors
Smoking
All centers together
Center 1
Center 2
Center 3
Alcohol consumption
All centers together

NS

Abbreviations: LE, lupus erythematosus; NS, not significant.


a Only significant values are given.

Table 3. Frequency of Smoking in Lupus Erythematosus (LE)


Patients and Controls According to Sex

Table 4. Cigarette Smoking in Lupus Erythematosus (LE)


Patients and Controls

No. of Smokers/Total No. (%)

No. of Pack-years

Sex

LE Patients

Controls

P Value, Test

Female
Male

52/80 (65.0)
27/28 (96.4)

74/160 (46.3)
33/56 (58.9)

.006, Fisher test


.001, Fisher test

often than female subjects among LE patients and controls (Breslow-Day test, P = .02). This could explain the
center effect observed in Table 1. Indeed, recruitment was
obviously very different among the 3 centers. Center 1
included significantly more male patients than centers
2 and 3, which included mostly female patients. However, this effect of center disappeared when the quantity
of tobacco use (pack-years) was analyzed in addition to
the prevalence (Table 4). Thus, when LE patients were
smokers, they smoked significantly more than controls
did (P=.002).
The prevalence of smoking among patients who met
4 or more ACR criteria and/or who had anti-nDNA antibodies was lower than in patients who met fewer than
4 ACR criteria (P=.002). Among the 43 patients (39.8%)
who met 4 or more ACR criteria, 23 (53.5%) were smokers and had smoked on average 5.5 pack-years. Among
the 65 patients (60.2%) who met fewer than 4 ACR criteria, 55 (84.6%) were smokers and had smoked on average 16 pack-years. Among the 39 patients with antinDNA antibodies, 24 (61.5%) were smokers. Among the
69 patients without anti-nDNA antibodies, 55 (79.7%)
were smokers. The LE patients with cutaneous involvement, fewer than 4 ACR criteria, and no anti-nDNA antibodies were those who smoked most. Patients who met
4 or more ACR criteria and who had anti-nDNA antibodies were those who smoked the least, even when compared with controls (Table 5 and Table 6).
An analysis of the prevalence of smoking within the
different subgroups of patients with cutaneous lesions
of LE showed no statistical difference (data not shown)
when we considered the prevalence of smoking and the
quantity of cigarettes consumed in pack-years, despite a
very high prevalence of smoking among LE patients with
the discoid disseminated (20 patients [86.9%]) and sub-

Center
All
1
2
3

LE Patients

Controls

11.7
14.4
8.7
9.9

a Indicates

7.0
7.2
6.6
7.0

P Value, Test
.002, Fisher test
.01 (LE) and
.13 (center),
Breslow-day test a

loss of effect of center.

acute (18 [69.2%]) subtypes. This is probably the consequence of the small size of the population in the different subgroups. Multiple logistic regression models and
simple analysis gave the same results. Thus, for ease of
presentation, only the latter were provided.
COMMENT

The current view of the etiology of LE is that several environmental factors act in a genetically predisposed individual to induce the disease. Our data suggest that
smoking is associated with an increased risk of LE,
whereas alcohol consumption is not. In this study, we
showed that cigarette smoking is particularly prevalent
in patients who met fewer than 4 ACR criteria and that a
dose effect exists.
Results concerning alcohol consumption and LE are
conflicting. Some studies demonstrated a protective
effect,3-5 whereas others showed no significant association,12,18 as in our study. In our medical practice, we have
observed that men and women with severe disseminated DLE and those who met fewer than 4 ACR criteria
of SLE were often alcoholic, but this finding was not confirmed in this study. Cigarette smoking, often associated with alcohol consumption, may be a confounding
factor.
Some previous studies have demonstrated that smoking is a risk factor for LE.3-7 The prevalence of current
smoking in LE patients varies from 17% to 46%, and a
recent meta-analysis of 9 studies (7 case-control studies
and 2 cohort studies)19 revealed an association between
cigarette smoking and LE (OR, 1.50; 95% CI, 1.09-

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Table 5. Cigarette Smoking in LE Patients According to ACR Criteria and in Controls


No. of Pack-years
LE Patients
Center
All
1
2
3

Meet 4 ACR Criteria

Meet 4 ACR Criteria

16.0
17.6
12.9
13.4

5.2
2.2
6.1
6.7

Controls

P Value, Test
.001, Fisher F distribution
.001 (ACR criteria),
.97 (center), and
.20 (sex), Breslow-Day test

7.0
7.2
6.6
7.0

Abbreviations: ACR, American College of Rheumatology; LE, lupus erythematosus.

Table 6. Cigarette Smoking in LE Patients According to the Presence or the Absence of Anti-nDNA Antibodies and in Controls
No. of Pack-years
LE Patients
Center
All
1
2
3

Without Anti-nDNA Antibodies

With Anti-nDNA Antibodies

15.0
16.6
14.0
13.5

5.0
4.8
5.8
2.6

Controls
7.0
7.2
6.6
7.0

P Value, Test
.001, Fisher F distribution
.001 (Presence of anti-nDNA antibodies),
.70 (center), and
.06 (sex), Breslow-Day test

Abbreviations: LE, lupus erythematosus; nDNA, nuclear DNA.

2.08). All of these studies focused on patients with SLE,


including mainly women who met 4 or more ACR criteria. Miot et al7 explored cigarette smoking in DLE patients who met fewer than 4 ACR criteria and they found
a very high prevalence of smoking (84.2%) in LE patients compared with the control population (33.5%) (OR,
14.4; 95% CI, 6.2-33.8). A strong association between LE
and tobacco was also observed in the study of Gallego et
al6 (OR, 12.2), who included patients comparable to those
of Miot et al.7
One source of the originality and strength of this study
is it was conducted in 3 centers with different patient recruitment. Center 1 included a huge proportion of male
patients, and overall most of the patients had cutaneous
LE without SLE (37 patients [69.8%]). Thus, center 1 is
representative of patients seen in general dermatology
practices. Center 2 included almost exclusively women
with SLE (21 patients [61.7%]), as seen in internal medicine or rheumatology departments, and center 3 included 11 patients (52.3%) who met 4 or more ACR criteria. Statistical analysis revealed that the difference in
the prevalence of cigarette smoking between the different centers seemed related not to LE subtype but to the
patients sex, with men smoking more than women. Thus,
sex obviously is a confounding factor that needs to be
addressed.
This effect of center also disappeared when we considered cigarette smoking according to the number of
pack-years. When LE patients smoke, they smoke more
than controls do. Our data also show that patients with
cutaneous LE who meet fewer than 4 ACR criteria are
those who smoke most compared with controls or compared with patients with anti-nDNA antibodies and/or
who meet 4 or more ACR criteria. The latter group of
patients are those who smoke the least, even when com-

pared with controls. Thus, our data strongly suggest that


cigarette smoking could have a greater effect on cutaneous manifestations of LE than on the extracutaneous signs
of the disease such as renal involvement. This observation suggests that the genetic background is much stronger and much more importantor at least differentin
patients who meet 4 or more ACR criteria than in patients with cutaneous LE who meet fewer than 4 ACR
criteria, in which environmental factors like cigarette
smoking could be crucial. This difference in patient recruitment could explain the discordant results of the association between LE and cigarette smoking in previous
studies. The fact that LE patients with anti-nDNA antibodies are those who smoke the least contradicts a study
showing that current cigarette smoking is associated with
DNA antibodies.20
Ninety-one percent of LE patients who were smokers
began to smoke a long time (mean, 14 years) before the
first manifestations of the disease, thus minimizing bias
associated with reactive habits induced by the disease. The
long time lapse between the initiation of smoking and the
first signs of disease suggests that there is a cumulative effect
involving an important accumulated smoking exposure.
The dose-response relationship between the number of
pack-years of smoking and the risk of LE is further supported by the strong statistical relationship with a packyear effect. The mean age for starting smoking was quite
precocious (18 years), with a high number of cigarettes
smoked a day (mean, 15 cigarettes a day).
Thus, this study provides strong evidence of a cumulative and dose effect, and cutaneous involvement seems
the main target affected by cigarette smoking. Hardy et
al4 suggested a dose effect, but the difference of cigarette smoking in pack-years between LE patients and controls did not reach significant difference in their study.

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How cigarette smoking could trigger LE remains unclear, but some hypotheses exist. Cigarette smoke contains more than 100 toxic and carcinogenic substances.
Some of them are aromatic amines, substances that are
also contained in drugs known to be associated with LE,21
especially subacute LE. Exposure to UV light is also a welldocumented trigger of LE, especially of the cutaneous
manifestations.1 Another study has shown that cigarette
smoke is phototoxic.22 From an immunological point of
view, cigarette smoking has very complex immunomodulatory effects, recently reviewed by Costenbader and Karlson.23 Furthermore, it has been known for many years
that antimalarials are less efficient in smokers.24,25 Although the metabolism of antimalarials is not well understood, it is possible they are inactivated by the cytochrome P450 enzyme complex. Polycyclic aromatic
hydrocarbons found in cigarette smoke are known potent inducers of the P450 enzyme complex.26 Finally, cigarette smoking may not be a risk factor per se, but predisposition to LE and dependency on cigarette smoking
could have a common genetic background, as discussed
by Boeckler et al14 and Fst et al,27 because a cluster of
genes for olfactory receptors implicated in smoking behavior and addiction is located close to the HLA antigen
class I region, of which some alleles are known genetic
risk factors for SLE.
Accepted for Publication: February 19, 2009.
Correspondence: Dan Lipsker, MD, PhD, Clinique
Dermatologique, 1, Place de lhopital, 67091 Strasbourg
CEDEX, France (dlipsker@gmail.com).
Author Contributions: All authors had full access to data.
Study concept and design: Boeckler and Lipsker. Acquisition of data: Boeckler, Cosnes, Francs, and Lipsker. Analysis and interpretation of data: Boeckler, Hedelin, and
Lipsker. Drafting of the manuscript: Boeckler and Lipsker.
Critical revision of the manuscript: Boeckler, Cosnes,
Francs, Hedelin, and Lipsker. Statistical analysis: Hedelin. Study supervision: Lipsker.
Financial Disclosure: None reported.
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