ARTHRITIS & RHEUMATISM
Vol. 46, No. 3, March 2002, pp 640–646
© 2002, American College of Rheumatology
Smoking and Disease Severity in Rheumatoid Arthritis
Association With Polymorphism at the Glutathione S-Transferase M1 Locus
Derek L. Mattey,1David Hutchinson,2Peter T. Dawes,1Nicola B. Nixon,1Sheila Clarke,1
June Fisher,1Ann Brownfield,1Julie Alldersea,3Anthony A. Fryer,3and Richard C. Strange3
Objective. To determine whether the relationship
between smoking and disease severity in women with
rheumatoid arthritis (RA) is associated with polymor-
phism at the glutathione S-transferase (GST) M1 locus.
Methods. Genotyping for GSTM1 was carried out
using polymerase chain reaction methodology on 164
women with established RA. Smoking history was ob-
tained on each patient. Radiographic damage was mea-
sured by the Larsen score, and functional outcome was
assessed by the Health Assessment Questionnaire
(HAQ). Data were analyzed by multiple regression
analyses, with correction for age and disease duration.
Results. Ever having smoked was associated with
a worse radiographic and functional outcome than was
never having smoked. Both past and current smoking
were associated with increased disease severity. Strati-
fication by GSTM1 status revealed that polymorphism
at this locus affected the relationship between smoking
and disease outcome measures. Patients who lacked the
GSTM1 gene and had ever smoked had significantly
higher Larsen and HAQ scores than did those who
lacked the gene and had never smoked. Radiographic
outcome in these patients was worse than that in
patients who had the GSTM1 gene and who had
smoked. The associations were not affected by correc-
tion for socioeconomic status. Rheumatoid factor (RF)
production was found to be associated with smoking in
only the GSTM1-null patients.
Conclusion. Our data suggest that disease out-
come in female RA patients with a history of smoking is
significantly worse than in those who have never
smoked. Smoking was associated with the most severe
disease in patients who carried the GSTM1-null poly-
morphism. This association may be due in part to a
relationship between the GSTM1 polymorphism and RF
production in smokers.
A number of studies have suggested that smoking
is a risk factor in susceptibility to rheumatoid arthritis
(RA) (1–10). While there have been fewer investigations
of the impact of smoking on disease outcome, 3 recent
studies have suggested that heavy smoking may influ-
ence overall RA severity (11–13). All of these studies
reported a relationship between smoking and rheuma-
toid factor (RF) positivity, nodule formation, and radio-
graphically determined joint damage. Smoking was also
associated with increased functional impairment (as
determined by scores on the Health Assessment Ques-
tionnaire [HAQ]), lower grip strength, and more pulmo-
nary disease (12,13), although these observations may be
related to comorbidity effects of smoking rather than the
severity of RA per se. In one study, the RF concentra-
tion was found to be positively correlated with the
number of years smoked (12), while another study
showed that the levels of IgA-RF and IgM-RF, but not
IgG-RF, were associated with the number of pack-years
The mechanism by which smoking influences RA
susceptibility/severity is unclear at present, although it
may have direct effects on the disease process by induc-
ing and/or increasing the production of RF or by pro-
Supported by the Arthritis Research Campaign and the
Haywood Rheumatism Research and Development Foundation.
1Derek L. Mattey, PhD, Peter T. Dawes, FRCP, Nicola B.
Nixon, Sheila Clarke, SRN, June Fisher, SRN, Ann Brownfield, BSc:
Staffordshire Rheumatology Centre, Stoke-on-Trent, UK;
Hutchinson, MRCP: University Hospital Aintree, Liverpool, UK;
3Julie Alldersea, Anthony A. Fryer, PhD, Richard C. Strange PhD:
Keele University School of Postgraduate Medicine, North Stafford-
shire Hospital, Stoke-on-Trent, UK.
Address correspondence and reprint requests to Derek L.
Mattey, PhD, Staffordshire Rheumatology Centre, The Haywood,
High Lane, Burslem, Stoke-on-Trent, Staffordshire ST6 7AG, UK.
Submitted for publication March 13, 2001; accepted in revised
form October 15, 2001.
ducing alterations in the immune system (3,14–17). The
influence of genetic factors on the association between
smoking and RA is unknown, although a recent study
reported that heavy cigarette smoking was particularly
associated with RA in patients who had no family history
of the disease (9). We postulate that genes associated
with detoxification or activation of chemicals in tobacco
smoke will be important. In this regard, our previous
finding that increased severity in RA is associated with a
null polymorphism at the glutathione S-transferase
(GST) M1 locus is of particular interest (18).
The GSTs are a widely expressed group of en-
zymes that catalyze the detoxification of xenobiotics via
glutathione conjugation. They are also believed to play
an important role in detoxifying products generated by
the activity of reactive oxygen species (ROS). There is
evidence that some allelic variants are associated with
differences in detoxification efficiency, and various can-
cer studies have suggested that polymorphism of
GSTM1 may influence the ability to detoxify chemicals
in cigarette smoke (19–21).
The GSTM1 enzyme detoxifies known or sus-
pected carcinogens found in tobacco smoke. These
include benzo[?]pyrene and other polycyclic hydrocar-
bons (19). The GSTM1 gene has 2 functional alleles
(GSTM1*A and GSTM1*B) and a nonfunctional null
allele caused by deletion of the GSTM1 sequence.
Homozygosity for GSTM1-null occurs in ?45–55% of
Caucasians. The GSTM1-null polymorphism has been
associated with increased risk of smoking-related can-
cers (19–25), and a synergistic interaction has been
observed between smoking and GSTM1-null on the risk
of coronary disease (26).
In this study, we sought to confirm that cigarette
smoking was associated with more severe disease in RA
and to test the hypothesis that the impact of smoking on
disease outcome is associated with polymorphism of the
GSTM1 gene which is involved in the detoxification of
chemicals in cigarette smoke. The hypothesis was devel-
oped a priori with GSTM1-null being considered as the
putative high-risk genotype. The study was performed
only on female RA patients. Most of the male RA
patients (?90%) in the population had been smokers,
and it was therefore not possible to test for statistically
significant differences between male patients who had
smoked and those who had not.
PATIENTS AND METHODS
Patients. The association between GSTM1 genotypes,
smoking, and disease severity was studied in 164 unrelated
female RA patients residing in North Staffordshire, UK. All
patients were Northern European Caucasians. The character-
istics of these patients are shown in Table 1.
The patients fulfilled the American College of Rheu-
matology (formerly, the American Rheumatism Association)
1987 criteria for RA (27) and were recruited in a clinic that had
been established to examine the effects of disease-modifying
antirheumatic drugs (methotrexate, sulfasalazine, hydroxy-
chloroquine, gold, and D-penicillamine). About 6.5% of the
patients were being treated with corticosteroids. Therapy was
administered as clinically indicated.
All patients had been examined annually for at least 5
years, and their disease had been extensively characterized.
Outcome measures were recorded at the final review and
consisted of assessments of functional status, using the HAQ
(28), and radiographic outcome, scoring radiographs of the
hands and feet according to the standard radiographs of
Larsen et al (29). RF levels were measured by nephelometry;
a level ?60 IU/ml was considered positive (30).
The Carstairs Deprivation Index (31,32) was used to
categorize the socioeconomic status of the patients. Carstairs
scores were obtained from the 1991 census small-area statistics
for the UK and assigned to each patient based on their
enumeration district of residence, which was identified from
the postal code address. The index is based on a composite of
4 variables: male unemployment, social class of head of
household, overcrowding, and access to a car. The Carstairs
scores in the RA population for this study ranged from ?4.6
(least deprived) to ?5.81 (most deprived).
Smoking history. A current and past smoking history
was obtained from each patient. Patients were initially classi-
fied by whether they had ever smoked or never smoked. Ever
smokers were those who had smoked at least 1 cigarette/day
for ?1 year, but not necessarily during the time of the study.
All patients who had ever smoked had started smoking before
the onset of RA. Those who had ever smoked were further
categorized into past and current smokers. Past smokers were
those who had stopped smoking at least 3 months before entry
into the study. Of the 35 past smokers, 21 had stopped smoking
before the onset of RA. The extent of smoking was quantified
in pack-years. One pack-year is equivalent to 20 cigarettes/day
for 1 year.
GST typing. Leukocyte DNA was extracted from blood
samples that had been collected into tubes containing EDTA.
GSTM1 genotypes were defined using a polymerase chain
reaction assay that identifies the GSTM1*0, GSTM1*A, and
GSTM1*B alleles (33). Patients were classified into those who
patients with rheumatoid arthritis
Demographic and clinical characteristics of the 164 female
Age at disease onset, years
Disease duration, years
Rheumatoid factor positive
Previous joint surgery
SMOKING, GSTM1 POLYMORPHISM, AND RA SEVERITY 641
expressed (GSTM1-1) and those who did not express
Statistical analysis. The association of disease severity
measures with GSTM1 genotypes and smoking was assessed
using multiple regression analyses, with adjustment for the
independent variables, age, and disease duration where appro-
priate. The influence of RF and the Carstairs Deprivation
Index were also examined by inclusion as independent vari-
ables in some of the regression models. Additional analyses
were performed after stratification by GSTM1 status. In some
analyses, we also examined the effect of interaction between
variables by use of multiple regression models that contained
the interaction term as well as the corresponding main effects.
Where appropriate, correction for potential multiple testing
errors was performed using Holm’s procedure (34). All analy-
ses were carried out using the Number Cruncher Statistical
Package for Windows (version 6.0.4; NCSS, Kaysville, UT), or
the PEPI software package (version 2.0) for epidemiologic
Frequency and extent of smoking in female RA
patients. About one-half (51.2%) of the patients had
ever smoked (Table 2). The number of smokers had
dropped to 29.9% by the time of the study. In this group,
the mean duration of smoking and the mean number of
pack-years were 38.9 years and 29.3 years, respectively
(Table 3), which were significantly greater than in past
smokers (23.5 years and 18.5 years, respectively). There
was a significantly higher frequency of seropositive
(RF?) disease among current smokers than among
those who had never smoked.
Relationship between smoking and disease sever-
ity in female RA patients. The mean Larsen score in
patients who had ever smoked was significantly higher
than that in patients who had never smoked (Pcorr?
0.01, corrected for age and disease duration) (Table 4).
The trend was similar in current smokers (Pcorr? 0.05).
The highest mean Larsen score (112.2) was found in past
smokers, and this was significantly higher than the
Larsen score in patients who had never smoked (Pcorr?
0.006). Using multiple regression analyses (corrected for
age and disease duration), we found that in patients who
had ever smoked, there was no association between the
Larsen score and the number of pack-years smoked (P ?
The HAQ scores showed a trend similar to that
of the Larsen scores. Ever, past, or current smokers had
significantly increased HAQ scores compared with those
who had never smoked (Table 4). Again, no association
was found between the HAQ score and the number of
pack-years smoked (P ? 0.68).
Influence of GSTM1 polymorphism on Larsen
and HAQ scores. Comparison of Larsen scores in
GSTM1-null and GSTM1-1 patients by multiple regres-
sion analysis revealed a trend toward more severe dis-
ease in GSTM1-null patients, which is similar to that
reported previously (18), although this did not achieve
significance after correction for age and disease duration
(99.4 versus 86.8; P ? 0.1). There was no significant
difference in the HAQ scores between the 2 subgroups
(1.57 versus 1.59).
female patients with rheumatoid arthritis
Frequency of cigarette smoking and seropositivity in 164
% positive for
* Odds ratio 2.5 (95% confidence interval 1.2–5.0), P ? 0.006 versus
never-smoked group (adjusted for age and disease duration).
† Odds ratio 3.2 (95% confidence interval 1.3–7.8), P ? 0.004 versus
never-smoked group (adjusted for age and disease duration).
Extent of cigarette smoking in female patients with rheu-
mean ? SD
mean ? SD
32.5 ? 13.3
23.5 ? 13.4
38.9 ? 9.7*
24.8 ? 16.1
18.5 ? 17.5
29.3 ? 14.4†
* P ? 0.0001 versus past-smoker group (corrected for age and disease
† P ? 0.001 versus past-smoker group (corrected for age and disease
tional outcome in female patients with rheumatoid arthritis*
Relationship between smoking and radiographic or func-
(n ? 80)
(n ? 84)
(n ? 35)
(n ? 49)
Larsen score 83.1 ? 47.2 104.7 ? 49.9† 112.2 ? 47.7‡ 99.3 ? 51.3§
HAQ score1.39 ? 0.81.77 ? 0.8‡1.86 ? 0.7¶1.71 ? 0.8#
* P values (versus the never-smoked group) were determined by
multiple regression analyses (adjusted for age and disease duration).
Pcorrvalues were corrected for multiple comparisons by Holm’s
procedure. HAQ ? Health Assessment Questionnaire.
† P ? 0.005 and Pcorr? 0.01.
‡ P ? 0.002 and Pcorr? 0.006.
§ P ? 0.05 and Pcorr? 0.05.
¶ P ? 0.009 and Pcorr? 0.018.
# P ? 0.02 and Pcorr? 0.02.
642MATTEY ET AL
To investigate whether polymorphism of the
GSTM1 gene influenced the response of RA to smoking,
we stratified patients by GSTM1 status (those expressing
versus those not expressing GSTM1) as well as by never
smoking or ever smoking. GSTM1-null patients who had
ever smoked had significantly higher Larsen (Pcorr?
0.012) and HAQ (Pcorr? 0.003) scores than GSTM1-
null patients who had never smoked (Table 5). Radio-
graphic outcome in GSTM1-null patients who had ever
smoked was also worse than that in GSTM1-expressing
patients who had ever smoked (Pcorr? 0.05), although
there was no significant difference in the HAQ scores. In
GSTM1-expressing patients, there were no significant
differences in the Larsen or HAQ scores between ever
smokers and never smokers.
Association between GSTM1 polymorphism,
smoking, and RF production. There was a significant
association between ever or current smoking and RF
positivity (P ? 0.006 and 0.004, respectively) after
correction for age and disease duration (Table 2). In all
smokers, the RF level was also associated with the
number of years of smoking (P ? 0.02). A linear
relationship between RF level and the number of pack-
years was not found, but smokers with ?20 pack-years
had significantly higher RF levels than those with ?20
pack-years (264.3 versus 99.9 IU; P ? 0.001).
We postulated that the development of more
severe disease in GSTM1-null patients who smoked
might be associated with a difference in their production
of RF. We therefore examined the association between
RF status and smoking in patients stratified by GSTM1
genotype. Using logistic regression analysis (adjusted for
age and disease duration), we found no significant
difference in RF status between ever smoking and never
smoking (67.7% versus 51.4%; odds ratio [OR] 1.9, P ?
0.2) in GSTM1-1 patients. However, in GSTM1-null
patients, there was a difference in RF status between
ever and never smoking (75.5% versus 51.2%; OR 3.1, P
? 0.01). Division into past and current smokers revealed
that this difference was specifically due to a difference
between current and never smoking in these patients
(83.9% versus 51.2%; OR ? 5.1, P ? 0.006) (Table 6).
No significant difference in RF status was found be-
tween current smoking and never smoking in GSTM1-1
patients (64.7% versus 51.4%; OR ? 1.7, P ? 0.4).
With regard to the amount of RF produced,
there was a significant association between current
smoking and RF levels in GSTM1-null patients (P ?
0.002), but no association in GSTM1-1 patients (P ?
0.4). Confirmation of the relationship between current
smoking and RF status in GSTM1-null patients (P ?
0.005) but not GSTM1-1 patients (P ? 0.3) was obtained
from a separate cohort of RA patients (n ? 134) with
early disease (median disease duration 1 year) (data not
Multiple regression models which included RF
(positive or negative) as well as GSTM1-null ? ever
smoking as independent variables showed that RF status
had the strongest association with the Larsen score after
correction for age and disease duration (Table 7). None-
theless, after correction for RF status, GSTM1-null ?
ever smoking remained associated with radiographic
outcome, although the significance levels were greatly
reduced. A similar observation was found for the HAQ
score, although the association with RF status was
weaker and age had a more significant effect than
disease duration (Table 8). These data suggest that the
functional outcome in female patients with rheumatoid arthritis,
stratified by GSTM1 status*
Relationship between ever smoking and radiographic or
patients Mean ? SD
patientsMean ? SD
82.8 ? 49.7
83.5 ? 44.9
112.8 ? 53.3†‡
90.8 ? 40.9
1.28 ? 0.8
1.50 ? 0.9
1.81 ? 0.8§
1.71 ? 0.7
* P values were determined by multiple regression analyses (adjusted
for age and disease duration). Pcorrvalues were corrected for multiple
comparisons by Holm’s procedure. GSTM1 ? M1 locus of glutathione
† P ? 0.006 versus GSTM1-0 ? never-smoked group; Pcorr? 0.012.
‡ P ? 0.05 versus GSTM1-1 ? ever-smoked group; Pcorr? 0.05.
§ P ? 0.001 versus GSTM1-0 ? never-smoked group; Pcorr? 0.003.
RF production in female patients with rheumatoid arthritis*
Relationship between GSTM1 status, current smoking, and
no. (%) of patients
mean ? SD IU
GSTM1-0 26/31 (83.9)† 19/37 (51.2) 284.7 ? 302.9‡ 69.8 ? 137.8
GSTM1-1 11/17 (64.7)21/41 (51.4) 175.4 ? 289.574.7 ? 138.1
* Values for rheumatoid factor (RF) frequency are the number
positive/number tested (%). P values were adjusted for age and disease
duration. GSTM1 ? M1 locus of glutathione S-transferase.
† Odds ratio 5.1 (95% confidence interval 1.6–15.3), P ? 0.006 versus
‡ P ? 0.002 versus never-smoked group.
SMOKING, GSTM1 POLYMORPHISM, AND RA SEVERITY643
association of GSTM1-null ? ever smoking with disease
severity is not due solely to RF status. However, the
possible contribution of other, as yet undiscovered,
confounder or modifier variables to the association of
this combination variable with the outcome measures
cannot be excluded.
Influence of socioeconomic status. We investi-
gated whether socioeconomic deprivation had any effect
on disease severity. There was no association between
the Carstairs Deprivation Index scores and radiographic
outcome in univariate or multivariate models (data not
shown). In contrast, the HAQ score was associated (P ?
0.015) with the Carstairs scores in models corrected for
age and disease duration only, but lost significance in
multivariate models containing GSTM1-null ? ever
smoking and RF status (Table 8). Removal of GSTM1-
null ? ever smoking from the latter model resulted in a
weakly significant association between the Carstairs and
HAQ scores (P ? 0.04).
We have shown in a well-characterized group of
female patients with RA that a history of cigarette
smoking is associated with more severe disease, although
the mechanism for this effect remains unclear. We also
provide evidence that the relationship between smoking
and disease severity in these patients is associated with
polymorphism at the GSTM1 locus.
Our data suggest that the risk of developing
severe disease in female RA patients is increased in
those who have the GSTM1-null polymorphism and who
have also smoked. The difference between these patients
and GSTM1-null patients who had never smoked was
highly significant, although significance levels were re-
duced after correction for RF status. In contrast, there
was no significant difference between smokers and non-
smokers who had the functional GSTM1-1 phenotype.
Also, in nonsmokers, there was no difference in outcome
between GSTM1-null and GSTM1-1 patients. Thus,
deletion of the GSTM1 gene per se does not appear to
influence RA severity, but does so only in individuals
who also smoke. The difference in disease outcome
between patients who have never smoked and those who
have ever smoked appears to be accentuated in individ-
uals with the GSTM1-null polymorphism. Given the
known role of the GSTM1 enzyme in detoxifying chem-
icals in cigarette smoke, this result suggests that such
substrates may have an important influence on the
progression of RA.
We confirmed the observations of other studies
(11,12), which found that patients who smoked were
more likely to be RF positive than were nonsmokers and
that the number of years smoked was associated with
levels of RF. Of particular interest was the finding that
the association between current smoking and RF status
was significant only in GSTM1-null patients, where
those who smoked had the highest levels of RF. The
correlation between smoking and RF has made it diffi-
cult to determine the independent predictive value of
each of these factors in relation to disease severity. From
our data, it is possible to speculate that lack of the
GSTM1 enzyme in smokers may promote increased RF
production through a failure to detoxify smoke-derived
chemicals (or their byproducts), which have the poten-
tial to damage IgG. Previous studies have suggested that
free radical–mediated alteration of IgG may stimulate
the formation of immune complexes with RF antibody,
thereby promoting tissue damage during rheumatoid
Saag et al (11) suggested that smoking may be
patients with rheumatoid arthritis*
Multivariate determinants of the Larsen score in female
GSTM1-0 ? ever smoked
* Multiple regression analysis with the Larsen score as the dependent
variable. The P values for rheumatoid factor (RF) and the M1-0 locus
of glutathione S-transferase (GSTM1-0) ? ever smoked represent the
significance of each variable compared with patients negative for that
variable or combination of variables (i.e., RF? versus RF?, GSTM1-0
? ever smoked versus the remainder). The F value for the model was
24.56 (P ? 0.0001).
patients with rheumatoid arthritis*
Multivariate determinants of the HAQ score in female
GSTM1-0 ? ever smoked
Carstairs Deprivation Index score
* Multiple regression analysis with the Health Assessment Question-
naire (HAQ) score as the dependent variable. The P values for
rheumatoid factor and the M1-0 locus of glutathione S-transferase
(GSTM1-0) ? ever smoked represent the significance of each variable
compared with patients negative for that variable or combination of
variables. The F value for the model was 9.88 (P ? 0.0001).
644MATTEY ET AL
more important in the initiation of erosive disease than
in the perpetuation of the disease process. The lack of an
obvious dose-related effect of smoking on the amount of
radiographic damage in patients in our study may add
some weight to this idea. However, our data also suggest
that if smoking is involved in the initiation process, it
leads to more severe disease than it does in patients in
whom smoking is not involved (particularly if the pa-
tients are GSTM1-null).
It might have been expected that increased expo-
sure to cigarette smoke would have led to increased
damage and more severe disease. However, the outcome
in past smokers was as severe as in those who continued
to smoke, even though the number of years smoked and
the number of pack-years were significantly lower in the
former group. Nonetheless, the mean duration and
amount of smoking in the past smokers was relatively
high and, compared with other studies, was close to the
levels considered to represent a history of heavy smok-
ing (7,11,12). There is evidence to suggest that individ-
uals who smoked in the past continue to produce RF,
even after cessation of smoking (12,38). Thus, tissue
damage mediated by RF complexes may continue long
after the initial stimulus for RF production has been
An alternative explanation for the lack of a
dose-related effect could be that some other factor(s) in
female smokers predisposes them to the development of
more severe RA, especially if they are GSTM1-null.
Potential confounders such as body mass index, estrogen
levels, oral contraceptive use, or alcohol intake may be
important, but without available data on these variables,
we were unable to test their effect in our study. How-
ever, a recent report from Karlson et al (7) suggested
that body mass index and oral contraceptive use were
not significant confounders in the association between
smoking and RA susceptibility. Other possible con-
founders such as diet or exposure to environmental
toxins may also have some influence but would be
difficult to quantify.
The observed associations do not appear to be
directly related to social deprivation, since adjustment
for socioeconomic status using the Carstairs Deprivation
Index did not affect the association between smoking
and disease severity in these patients. This is consistent
with the report by Saag et al (11), who found that the
association of smoking with radiographic changes or RF
positivity did not vary with any sociodemographic factors
tested. There was no association between the Carstairs
score and radiographic outcome with or without inclu-
sion of GSTM1-null ? smoking in our regression mod-
els, although we did find a relationship between func-
tional outcome and the Carstairs score after exclusion of
GSTM1-null ? smoking. This is consistent with previous
studies that showed a relationship between functional
outcome and social deprivation (39,40). However, those
studies did not investigate the influence of smoking, and
our data suggest that the relationship between social
deprivation and functional outcome is at least partly due
to the influence of smoking. It needs to be borne in mind
that the HAQ score may not be a specific indicator of
the functional impact of RA severity per se. This may be
particularly true among patients who smoke, given that
smoking is likely to have adverse effects on general
health and function.
One limitation of this study is its cross-sectional
nature and the difficulty in establishing cause and effect.
It has been argued that such studies are subject to
misclassification of smoking status and that patients with
very mild disease (who no longer seek medical care) or
patients with very severe disease (who may have died)
are underrepresented (41). While prospective studies
may overcome some of these difficulties, they tend to be
of relatively short duration and may not properly address
the long-term impact of smoking on disease severity.
They may also suffer from the difficulty of classifying
RA in patients with early inflammatory polyarthritis. We
do not believe that misclassification of smoking status is
a problem in our current study, especially since we found
no difference in disease outcome between past and
current smokers. However, our study is clearly limited to
women with well-established RA in one particular geo-
graphic area, and further studies of different populations
are needed to establish the generalizability of these
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