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CLINICAL RESEARCH STUDY

Smoking Intensity, Duration, and Cessation, and the Risk

of Rheumatoid Arthritis in Women

Karen H. Costenbader, MD, MPH,a,b Diane Feskanich, ScD,b Lisa A. Mandl, MD, MPH,c Elizabeth W. Karlson, MDa,b

aDivision of Rheumatology, Immunology, and Allergy, Section of Clinical Sciences, Robert B. Brigham Arthritis and Musculoskeletal

Diseases Clinical Research Center, Brigham and Womens Hospital, Harvard Medical School, Boston, Mass; bChanning Laboratory,

Department of Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston, Mass; cDivision of Rheumatology,

Department of Medicine, Hospital For Special Surgery, Cornell Weill Medical College, New York.

ABSTRACT

BACKGROUND: Cigarette smoking has been associated with rheumatoid arthritis (RA), but the impor-

tance of smoking intensity, duration, and time since quitting, and whether the risk is primarily for

rheumatoid factor (RF) seropositive versus seronegative RA are still unclear.

METHODS: We conducted a prospective analysis of smoking and the risk of RA among 103,818 women

in the Nurses Health Study. A total of 680 RA cases, diagnosed from 1976 and 2002, were confirmed

using a questionnaire and medical record review. Sixty percent were RF positive. Cox proportional hazards

models calculated the relative risks (RRs) of RA with smoking, adjusting for reproductive and lifestyle

factors.

RESULTS: The RR of RA was significantly elevated among current (RR 1.43 [95% confidence interval

1.16-1.75]) and past smokers (RR 1.47 [95% confidence interval 1.23-1.76]), compared with never

smokers. The risk of RA was significantly elevated with 10 pack-years or more of smoking and increased

linearly with increasing pack-years (P trend .01). A greater number of daily cigarettes and longer

duration of smoking were associated with increased risk. The effect of smoking was much stronger among

RF-positive cases than among RF-negative cases. The risk remained elevated in past smokers until 20 years

or more after cessation.

CONCLUSIONS: In this large cohort, past and current cigarette smoking were related to the development

of RA, in particular seropositive RA. Both smoking intensity and duration were directly related to risk,

with prolonged increased risk after cessation. 2006 Elsevier Inc. All rights reserved.

KEYWORDS: Rheumatoid arthritis; Risk factors; Epidemiology; Cigarette smoking; Rheumatoid factor

Rheumatoid arthritis (RA) is an autoimmune disease char-

acterized by chronic, destructive, and debilitating arthritis,

occasionally with systemic involvement. RA is the most

common inflammatory arthritis, affecting approximately

1% of the adult population.1 The cause of RA is unknown,

but it is presumed that environmental factors contribute toits development in the genetically predisposed.

Case-control studies over the past 20 years have inves-

tigated the relationship between cigarette smoking and the

development of RA.2-10 In these studies, the association of

cigarette smoking with the development of RA seems to be

stronger for men than for women, and several studies have

not found an elevated risk of RA associated with cigarette

smoking in women.3,4,7,8 In addition, the risk of RA asso-

ciated with smoking has been reported to be highest for

rheumatoid factor (RF) seropositive RA4,6,8-10 and in those

Supported by National Institutes of Health grants AR42630, CA87969,

AR36308, R01 AR49880, and P60 AR47782. Dr. Costenbader is the

recipient of an American College of Rheumatology/Arthritis Foundation

Physician Scientist Development Award, a Kirkland Fellowship, and a

Harvard Medical School/Eli Lilly 50th Anniversary Scholars in Medicine

Award. Dr. Mandl is a recipient of an American College of Rheumatology

Clinician Investigator Award.

Requests for reprints should be addressed to Karen H. Costenbader,

MD, MPH, Brigham and Womens Hospital, Division of Rheumatology,

Immunology and Allergy, 75 Francis St., Boston, MA 02115.

E-mail address: [email protected].

0002-9343/$ -see front matter 2006 Elsevier Inc. All rights reserved.

doi:10.1016/j.amjmed.2005.09.053

The American Journal of Medicine (2006) 119, 503-511


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who carry a copy of the human leukocyte antigen, DR

subregion (HLA-DR) shared epitope.10

Cohort studies also have examined cigarette smoking as

a risk factor for RA. In 1990, Hernandez Avila and col-

leagues11 reported an increased risk of RA and undifferen-

tiated polyarthritis in a subset of

women who currently smoked 15

to 24 cigarettes per day in theNurses Health Study, although

they did not find any significant

associations with having ever

smoked or in other subgroups. In a

retrospective analysis in the

Womens Health Study, a ran-

domized controlled trial of low-

dose aspirin and vitamin E for the

prevention of cardiac disease, in-

creased duration of cigarette

smoking, more so than smoking

intensity, was associated with anincreased risk of RA.12 In the

Iowa Womens Health Study, a

cohort study in elderly women,

both increasing intensity and du-

ration of smoking were associated

with RA. The effect of smoking

on the risk of RA seemed to last up to 10 years after

smoking cessation, after which the risk of RA returned to

that of never smokers.13

Exposure to passive cigarette smoke (environmental to-

bacco) has been associated with chronic diseases including

asthma,14 cancer,15,16 and heart disease,17,18 but its associ-ation with RA has never been investigated. Thus, we sought

to further explore the relationship between cigarette smok-

ing, the role of intensity, the duration, and the effect of

smoking cessation, as well as that of exposure to passive

smoke, and the development of RA in women aged 30 to 81

years in a large prospective cohort study.

METHODS

Study PopulationThe Nurses Health Study is a prospective cohort of 121,700

female nurses aged 30 to 55 years in 1976, when the studybegan. Information was collected from the subjects by bi-

ennial questionnaires regarding diseases, lifestyle, and

health practices. Follow-up of the original cohort has been

greater than 94% through 2002.19 All aspects of this study

were approved by the Partners HealthCare Institutional

Review Board.

Identification of Rheumatoid ArthritisFrom 1976 to 1982, participants self-reported a diagnosis of

RA or other connective tissue diseases (CTDs) including

systemic lupus erythematosus, mixed CTD, scleroderma,

polymyositis, dermatomyositis, or Sjgren syndrome in awrite-in section of the questionnaire. Beginning in 1982,

participants have been specifically asked whether they have

a physician diagnosis of RA. For this study, we contacted

11,966 women reporting RA and 1673 women reporting

any other CTD on any of the biennial questionnaires from

1976 to 2002. We requested permission to review their

medical records and that they

complete the CTD screening ques-

tionnaire (CSQ), which includes 6questions on symptoms of RA.20

The CSQ was scored as positive if

4 of 6 responses to these questions

were positive. It was scored as

possible if 3 of 6 were positive,

in which case follow-up CSQs

were mailed to the participant in

the following cycles. In total, after

5 mailings, 10,455 (77%) of the

women who had self-reported RA

or any other CTD responded. Af-

ter excluding subjects who deniedthe diagnosis of RA (n 2239),

had RA diagnosed before 1976 (n

475), denied permission for

record review (n 1066), or had a

negative CSQ for RA symptoms

(n 3052), we requested medical

records from 3623 women and obtained 2737 (76%) records

with adequate information. Two rheumatologists trained in

chart abstraction independently conducted a medical record

review examining the charts for the American College of

Rheumatology diagnostic criteria for RA.21 Subjects with 4

of the 7 diagnostic criteria documented in the medical

record were considered to have definite RA. We confirmed

807 new cases of definite RA diagnosed between 1976 and

2002 for a case confirmation rate of 29% of the medical

records reviewed and 7% of the original self-reports.

Population for AnalysisFor all analyses, we excluded prevalent cases of RA diag-

nosed before June 1976, nonresponders, and women who

reported any CTD that was not subsequently confirmed to

be RA by medical record review. We excluded women who

reported any cancer (except nonmelanoma skin cancer) at

baseline or during follow-up because cancer and its treat-

ment can affect smoking behavior. Women were censored

when they failed to respond to any subsequent biennial

questionnaire. When women failed to report smoking status

during a questionnaire cycle, we did not include these per-

son-years in the analysis. Thus, the final group studied

included 103,818 women followed from 1976 to 2002 and

680 cases of incident RA among those women. The overall

prevalence of RA cases diagnosed after 1976 (when the

women were aged 35-50 years) was 0.8%, which is close to

the expected 1% to 2% prevalence rate of RA expected in amainly white adult female population.1,22

CLINICAL SIGNIFICANCE

Both increasing duration and intensityof cigarette smoking increase the risk ofrheumatoid arthritis in women.

With10 pack years of smoking, the riskof rheumatoid arthritis rises and does soin a dose-dependent manner.

After smoking cessation, it takes 20years for the risk of rheumatoid arthritis

to return to that of never smokers. Most of the risk associated with smoking

is for rheumatoid factor positive rheu-matoid arthritis.

503.e2 The American Journal of Medicine, Vol 119, No 6, June 2006


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Information on Smoking Exposures andPotential Confounding VariablesAll exposure information was self-reported on the mailed

questionnaires administered every 2 years since 1976. On

the initial Nurses Health Study questionnaire, participants

reported whether they were current smokers or had ever

smoked in the past and the age at which they began to

smoke. Current smokers were asked for the number of

cigarettes typically smoked per day, and former smokers

reported the age at which they stopped smoking and the

number of cigarettes smoked per day before quitting. On

each subsequent questionnaire, participants reported

whether they currently smoked and the number of cigarettes

smoked per day. From these reports, we calculated smoking

duration, pack-years of smoking (product of years of smok-

ing and packs of cigarettes per day), time since quitting, and

age at quitting. No data from participants who did not report

smoking information were included for the specific ques-

tionnaire cycles missing this information. However, when

smoking information was later provided it was updated

correctly to account for the missing years. All smoking

variables were time-varying. The information was updated

every 2 years, because smokers often stop and restart smok-

ing. Questions concerning passive cigarette smoke exposure

were asked once in 1982. Participants were asked whether

neither of their parents, their mother only, their father only,

or both parents had smoked at home. Subjects also were

asked to report the number of years they had lived with a

smoker (including as a child and as an adult) and whether

they were never, occasionally, or regularly exposed to cig-

arette smoke at work.Important reproductive covariates were chosen on the

basis of our past findings of associations between reproduc-

tive factors and the risk of developing RA in this cohort.23

Age at menarche, regularity of menses between the ages 20

and 35 years, parity, duration of breastfeeding, postmeno-

pausal hormone use, and body mass index were included as

potential confounders of the smoking and risk of RA rela-

tionship. Alcohol intake and socioeconomic status were

included as covariates in the multivariate models. Alcohol

intake was reported every 2-year cycle starting in 1980 and

classified in grams per day. Fathers occupation, asked in

1976, was chosen as a proxy for childhood socioeconomicstatus. There are no data on household income in the

Nurses Health Study, and because all the women are

nurses, the range of adult socioeconomic status is limited.

Fathers occupation was classified as professional (includ-

ing professional and managerial jobs) or nonprofessional

(including clerical, sales, craftsman, service, laborer,

farmer, and at-home jobs).

Statistical AnalysisPerson-years of follow-up accrued from the date of return of

the 1976 baseline questionnaire until the date of diagnosis

of RA, as defined in the medical record; death; the report ofcancer (excluding nonmelanoma skin cancer); or loss to

follow-up, defined as no further return of questionnaires.

When women failed to report smoking status during a ques-

tionnaire cycle, we did not include these person years in the

analysis. Age-adjusted and multivariate Cox proportional

hazards models were used to study the association between

RA (developing from ages 30-81 years) and cigarette smok-

ing. Information from each 2-year questionnaire was used to

analyze the risk of RA in the next 2-year cycle. Age wascategorized as less than 50, 50-54, 55-59, 60-64, and 65 or

more years in age-adjusted models and in months in mul-

tivariate models. Tests for linear trend were calculated ex-

cluding the reference category of never smokers and using

continuous values for smoking exposure. In multivariate

models that adjusted for multiple smoking variables, never

smokers were excluded. The correlation between the time

since quitting cigarettes and smoking duration was mea-

sured using a Spearman correlation test.

Stratified analyses were used to examine the effect of age

at which smoking ceased and the subsequent risk of RA.

Stratified analyses also were used to investigate the associ-ation of smoking with RF seropositive and RF seronegative

RA separately, to examine the effect of living with a smoker

separately among never and ever smokers, and to examine

the risks in premenopausal compared with postmenopausal

women. In addition, to analyze the effect of excluding the

women who had reported cancer, a subanalysis in which

they were included was performed. SAS version 6 was used

for all analyses.24

RESULTS

We examined characteristics of the women participating inthe Nurses Health Study according to smoking status in

1990, the approximate midpoint of the follow-up period in

this analysis (Table 1). Body mass index was lower among

current smokers than it was among never and past smokers.

Current smokers were less likely to be premenopausal, and

among the parous women, they were the least likely to have

breastfed for more than 12 months during all pregnancies. In

addition, there were no important differences in the charac-

teristics (listed in Table 1) of those women who responded

to our additional mailings (n 10,455), compared with

those who did not (n 3184).

Of 680 RA cases with a mean age at diagnosis of 56 (9)years, 401 (59%) were seropositive and 207 (30%) had

radiographic changes characteristic of RA. Most of the RA

cases (83%) had been diagnosed by a member of the Amer-

ican College of Rheumatology.

The age-adjusted relative risk (RR) of developing RA

was 1.49 (95% confidence interval [CI] 1.28-1.75) among

women who had ever smoked, and the risk was similarly

elevated in both current and past smokers (Table 2). Ad-

justing for the multiple potentially important covariates in-

cluded in the multivariate models did not substantially alter

risk estimates (multivariate RR of ever smoking 1.46 [95%

CI 1.24-1.71]). In age-adjusted and multivariate models,higher pack-years were associated with increasing risk of

503.e3Costenbader et al Smoking Intensity, Duration, Cessation, and RA


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Table 1 Age-standardized Characteristics of the Nurses Health Study Women in 1990 Within Categories of Smoking Status

(n 88,520)

Never n 38,677 Past n 33,076 Current n 15,425

Age, mean 56.3 56.6 55.9Body mass index, mean 25.9 25.9 24.7Alcohol intake, g/d, mean 3.6 4.0 4.3

Age at menarche years, mean 12.4 12.4 12.5Pack-years of cigarettes smoked, mean 0 17.2 38.3Average number of cigarettes per day 0 16.4 18.9Duration of smoking, y 0 20.7 36.1Father in professional/managerial occupation (%) 24 27 26Usually/very irregular menses at age 20-35 y (%) 12 12 12Nulliparous (%) 6 6 7Breastfeeding 12 mo (among parous women) (%) 19 15 11Premenopausal (%) 25 24 20Postmenopausal hormone use (among

postmenopausal women) (%)

33 36 32

Parent smoked at home* (%) 50 59 57Lived 30 years with a smoker* (%) 7 11 18Regularly exposed to smoke at work* (%) 20 21 32

*Assessed in 1982.

Table 2 Relative Risk of Rheumatoid Arthritis by Pack-years of Smoking Among Women in the Nurses Health Study, 1976-2002

(N 103,818)

Cases Person-years

Age-adjusted RR

(95% CI*)

Multivariate RR

(95% CI*)

Smoking statusNever 237 1,020,587 1.0 1.0

Ever 443 1,270,172 1.49 (1.28-1.75) 1.46 (1.24-1.71)Current 163 491,801 1.46 (1.20-1.79) 1.43 (1.16-1.75)Past 280 778,371 1.50 (1.26-1.79) 1.47 (1.23-1.76)

Pack-yearsNever 237 1,020,587 1.0 1.01-10 103 423,669 1.08 (0.86-1.36) 1.07 (0.85-1.36)11-20 79 255,980 1.37 (1.06-1.77) 1.35 (1.04-1.74)21-30 90 198,998 1.97 (1.55-2.52) 1.93 (1.50-2.47)31-40 56 155,145 1.45 (1.08-1.95) 1.36 (1.01-1.83)40 98 196,860 1.99 (1.57-2.53) 1.86 (1.46-2.38)P for trend P.001 P.01Pack-years current smokers

Never 237 1,020,587 1.0 1.01-20 30 144,797 1.04 (0.70-1.55) 1.04 (0.70-1.53)

21-40 72 196,350 1.62 (1.24-2.11) 1.54 (1.18-2.02)40 59 133,011 1.76 (1.32-2.35) 1.65 (1.23-2.21)P for trend P .01 P .01Pack-years past smokers

Never 237 1,020,587 1.0 1.01-10 94 365,772 1.11 (0.88-1.41) 1.11 (0.87-1.42)11-20 58 169,080 1.44 (1.08-1.92) 1.40 (1.05-1.87)21-40 74 157,793 1.90 (1.46-2.47) 1.79 (1.37-2.33)30 39 63,848 2.46 (1.74-3.48) 2.29 (1.62-3.24)

P for trend P.001 P.001

*Ninety-five percent confidence interval.

Adjusted for body mass index (22, 22 to 25, 25 to 30, 30 to 35, 35 kg/m2), alcohol intake (none, 5, 5 to 9, 9 to 15, 15 g/d),

fathers occupation (professional, nonprofessional), age at menarche (12, 12, 12 y), regularity of menses (very regular, usually regular, usually

irregular, very irregular), duration of breastfeeding (nulliparous, parous-never, 1-3 mo, 4-11 mo, 12-23 mo, 24 mo), postmenopausal hormone use

(premenopausal, postmenopausal-never, postmenopausal-past, postmenopausal-current).P for trend excludes never smokers.3



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RA with a significant dose-response trend (P trend .01).

The highest risk was observed in past smokers of 40 pack-

years or more (multivariate RR 2.29 [95% CI 1.62-3.24]).

To determine whether the intensity or the duration of

cigarette smoking contributed more to the risk of RA, we

examined these 2 components comprising pack-years sepa-

rately (Table 3). In age-adjusted models, the risk of RA was

elevated among current and past smokers of 15 cigarettes ormore per day, with a significant linear trend for increasing

risk with increasing amount smoked (P trend .001 in both

models). The risk of developing RA trended upward with

increasing duration of smoking among past smokers (P

trend .001) and current smokers (P trend .04). The results

of multivariate-adjusted models were similar to the age-

adjusted models (Table 3). In the multivariate models lim-

ited to ever smokers in which smoking amount and duration

were mutually adjusted for one another, both factors con-

tribute independently to the RR of RA (Table 3). The

increased RR of RA was demonstrated up to 20 years after

cessation of cigarette smoking in both age-adjusted and

multivariate models limited to ever smokers (Table 3).

Smoking duration and time since quitting were highly neg-

atively correlated (Spearman correlation 0.62).

To rule out an effect of the onset of RA symptoms on

smoking habits, we performed 2 sensitivity analyses: ending

all follow-up data 2 years before the date of RA diagnosis;

and ending all follow-up data at the first onset of RA

symptoms (date of RA symptoms from medical record re-

view available for 639/680 cases). In these sensitivity anal-

yses, the results were essentially unchanged. When fol-

low-up was stopped 2 years before the diagnosis of RA, thefully adjusted RR of RA was 1.47 (95% CI 1.19-1.82)

among current smokers and 1.50 (95% CI 1.25-1.80) among

past smokers. When follow-up ended at the date of first

symptoms of RA, the fully adjusted RR of RA was 1.37

(95% CI 1.10-1.71) among current smokers and 1.43 (95%

CI 1.19-1.73) among past smokers.

In an analysis stratifying the cases of RA by the presence

or absence of RF, the RRs of seropositive RA associated

with past and current smoking and with increasing pack-

years were greater than those observed for all cases of RA

and similar strong trends were observed (Table 4). Strong

positive associations also were observed for intensity andduration of smoking (data not shown). In comparison, the

RRs of seronegative RA associated with cigarette smoking

were not as elevated for past and current smokers and no

clear dose response was observed for pack-years (Table 4).

To investigate the effect of menopausal status on the risk

of developing RA associated with cigarette smoking, Cox

proportional hazards models stratified by menopausal status

were performed. The risk of developing RA during the

premenopausal years for all women in the cohort for ever

smokers (multivariate RR 1.48 [95% CI 1.07-2.06]) was not

substantially different than the risk among postmenopausal

women ever smokers (multivariate RR 1.53 [95% CI 1.25-1.88]). In a sensitivity analysis including the women with

cancer who had been excluded (65 cases of verified RA had

been excluded), the risk estimates were very similar (mul-

tivariate RR among ever smokers 1.47 [95% CI 1.26-1.72]).

Analyses examining passive cigarette smoke exposure

included 453 incident RA cases diagnosed since 1982, the

year in which this question was included on the question-

naire. Living with a parent smoker as a child and being

exposed to smoke regularly at work were not associatedwith significantly increased risks of RA. Smokers were

almost twice as likely to have lived with a smoker than

nonsmokers, reducing the power to examine the risk of

passive exposure to cigarette smoke in nonsmokers. Among

nonsmokers, there was a suggestion that living with a

smoker for greater than 30 years was associated with an

increased risk of RA, although not significantly so (multi-

variate RR 1.59 [95% CI 0.92-2.74]), and no dose effect

was seen (Table 5).

To quantify the influence of cigarette smoking exposure

on the incidence of RA in this cohort of women, population

attributable risk estimates were computed. Two hundrednew cases of RA per 100,000 in the population could have

been prevented during the 26 years of follow-up of the

103,818 women included in this study. Given the genotypic

mixture of this particular cohort, this represents 25% of the

new cases of RA (population attributable risk percentage)

that may have been prevented had none of these women

smoked.

DISCUSSIONIn this large cohort of female nurses, both past and current

cigarette smoking were associated with similarly elevatedrisks of RA of more than 40%. A strong dose response

between pack-years of smoking and the risk of RA was

demonstrated. Both smoking intensity and smoking dura-

tion contributed to this effect, and smoking greater than 15

cigarettes a day and greater than 20 years were both asso-

ciated with increased risk. The risk of incident RA remained

substantially elevated until 20 years after smoking cessa-

tion. This suggests that a threshold quantity of cigarette

smoke exposure may exist in those genetically at risk for

RA and that, once attained, the risk remains elevated for

years to come. In this study, the first to investigate the

relationship between passive smoke exposure and RA, apossible association between long-term passive smoke ex-

posure and elevated risk of RA was suggested, although this

question should be addressed in further studies. Our assess-

ment of the independent effect of passive smoke exposure,

however, was limited by the small proportion of nonsmok-

ers who had had passive smoke exposure and by the fact

that questions concerning passive smoke exposure were

asked only once in 1982.

We also observed that the risk associated with smoking

was much higher for seropositive RA than for seronegative

RA, as has been observed by others.4,6,8-10 The relationship

between cigarette smoke exposure and RF, antibodies di-rected against the Fc portion of immunoglobulin G, is in-



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teresting and complex. Cigarette smoking has been linked to

the presence of RF in the blood of healthy individuals

without RA,25-27 and it is not clear whether this represents

a pre-RA state. Although seropositive RA is a relatively

homogeneous phenotype, more likely to be associated with

the HLA-DR4 shared epitope and joint erosions, destruc-

tion, and extra-articular disease,28 seronegative RA is more

challenging to diagnose and, in studies such as these, may

represent a more heterogeneous collection of diseases. Vi-

ral, psoriatic, reactive, and crystal-associated arthritides

may all mimic RA, and time is often necessary for diagnosis

confirmation. The finding that cigarette smoking is associ-

ated with a greater elevation of the risk of seropositive than

seronegative RA underscores the likelihood that seronega-

tive RA is a heterogenous and distinct condition.

Some of the case-control studies in the past have re-

ported the risk of RA is elevated in male, but not in female,

smokers,4,7,8 but our prospective cohort study demonstrates

that cigarette smoking elevates the risk of RA in women as

well. In these past studies, smoking was categorized as

never/past/current or never/ever, and associations between

the development of RA and the intensity and/or duration of

cigarette smoking were not investigated.3,4,7,8 Given that the

most substantial risk of RA is posed by the heaviest smok-

Table 4 Relative Risk of Developing Rheumatoid Factor Positive or Negative Rheumatoid Arthritis by Smoking Status and Pack-

years of Smoking Among Women in the Nurses Health Study, 1976-2002 (N 103,818)

RF positive RA RF negative RA

Cases Person-years

Multivariate RR*

(95% CI) Cases Person-years

Multivariate RR*

(95% CI)

Smoking statusNever 136 1,019,108 1.0 101 1,018,751 1.0Ever 266 1,267,761 1.59 (1.29-1.97) 177 1,266,650 1.28 (1.00-1.65)Current 100 490,817 1.58 (1.21-2.06) 63 490,078 1.23 (0.88-1.70)Past 166 776,944 1.60 (1.27-2.02) 114 776,572 1.31 (1.00-1.73)

Pack-yearsNever 136 1,019,108 1.0 101 1,018,751 1.01-10 56 423,026 1.05 (0.76-1.43) 47 422,900 1.10 (0.78-1.57)11-20 50 255,482 1.57 (1.13-2.18) 29 255,199 1.08 (0.71-1.64)21-30 55 198,507 2.18 (1.59-2.01) 35 198,244 1.61 (1.09-2.38)31-40 35 154,874 1.55 (1.06-2.25) 21 154,575 1.12 (0.69-1.80)40 63 196,509 2.22 (1.63-3.02) 35 196,347 1.43 (0.96-2.12)

P for trend P.01 P .55

*Adjusted for BMI (22, 22 to25, 25 to30, 30 to35,35 kg/m2), alcohol intake (none,5, 5 to9, 9 to15,15 g/d), fathers occupation

(professional, nonprofessional), age at menarche (12, 12, 12), menstrual regularity (very regular, usually regular, usually irregular, very irregular),duration of breastfeeding (nulliparous, parous-never, 1-3 mo, 4-11 mo, 12-23 mo, 24 mo), postmenopausal hormone use (premenopausal, postm-

enopausal-never, postmenopausal-past, postmenopausal-current).

Ninety-five percent confidence interval.

P for trend excludes never smokers.

Table 5 Relative Risk of Rheumatoid Arthritis According to Number of Years Lived with Smoker Among Women in the Nurses

Health Study, 1982-2002 (n 79,283)

Ever Smokers Never Smokers

Years lived with

smoker Cases Person-years

Age-adjusted RR

(95% CI*)

Multivariate RR

(95% CI*) Cases Person-years

Age-adjusted RR

(95% CI*)

Multivariate RR

(95% CI*)

Never 73 277,530 1.0 1.0 35 130,664 1.0 1.01-9 28 107,390 0.99 (0.64-1.53) 1.04 (0.67-1.63) 54 134,964 1.50 (0.98-2.29) 1.53 (0.98-2.40)10-19 20 97,675 0.79 (0.48-1.29) 0.75 (0.46-1.25) 62 175,892 1.35 (0.89-2.05) 1.38 (0.90-2.12)20-29 16 83,079 0.70 (0.41-1.21) 0.67 (0.39-1.17) 79 180,723 1.46 (0.98-2.16) 1.44 (0.95-2.20)30 20 51,540 1.38 (0.80-2.38) 1.59 (0.92-2.74) 57 127,456 1.37 (0.89-2.12) 1.46 (0.92-2.32)P for trend .38 .77 .59 .27

*Ninety-five percent confidence interval.

Adjusted for BMI (22 [ref], 22 to25, 25 to30, 30 to 35,35 kg/m2), alcohol intake (none [ref],5, 5 to9, 9 to15,15 g/d), fathers

occupation (professional, nonprofessional), age at menarche (12, 12 [ref], 12), parity (nulliparous [ref], parous, missing), duration of breastfeeding

(nulliparous, parous-never [ref], 1-3 mo, 4-11 mo, 12-23 mo, 24 mo), postmenopausal hormone use (premenopausal [ref], postmenopausal-never,

postmenopausal-past, postmenopausal-current), and pack-years of smoking, continuous (among ever smokers).P for trend excludes those who never lived with smoker.



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ing and that women, until recently, have been lighter smok-

ers than men,29-31 the association between smoking inten-

sity and RA in women may have been overlooked.

When Hernandez Avila and colleagues11 investigated

cigarette smoking, along with several other exposures, in

the Nurses Health Study from 1976 to 1984, they reported

suggestive but nonsignificant findings: age-adjusted RR for

RA in current smokers was 1.3 (95% CI 0.9-2.1) and 1.5among former smokers (95% CI 0.9-2.3).11 Only in the

subgroup of current smokers of 15 to 24 cigarettes per day

did they find a significant association with the risk of RA

and undifferentiated polyarthritis. They had far fewer RA

cases at that time, and the inclusion of this latter group of

nonspecific cases may have biased their results toward the

null.

The Iowa Womens Health Study13 and a Swedish case-

control study using incident RA cases9 reported that the risk

of developing RA in those who had quit smoking more than

10 years earlier was not significantly elevated above that

seen in those who had never smoked. In the Nurses Health

Study, however, we did not observe the risk of RA to

decline below that of current smokers until 20 or more years

after smoking cessation. It seems that a certain threshold

amount of cigarette smoke exposure is necessary and that

once attained, this exposure poses a latent, rather than an

instantaneous, hazard and that the risk does not decrease

with time until long after cessation of exposure.

The biochemical and cellular pathways by which ciga-

rette smoke augments the risk of RA have not been delin-

eated. Cigarette smoke contains hundreds of potentially

toxic components, including tars, resins, and free radicals,and is known to activate endogenous sources of free radi-

cals, as well as neutrophils, monocytes, and platelets.32-36

Abnormalities in T-cell function,37,38 reduction in natural

killer cells,39 impairment of humoral immunity,39-41 and

elevated levels of inflammatory markers such as interleu-

kin-6 and C-reactive protein42,43 have been observed in

smokers. Heavy cigarette smoking may act as a trigger in

the genetically predisposed to seropositive RA, a likely

second hit in those who are at already elevated risk. In a

Swedish study, cigarette smoking dramatically increased

the RR of seropositive RA (but not seronegative RA) to 7.5

(95% CI 4.2-13.1) in those who carried the HLA-DR4shared epitope, the strongest known genetic risk factor for

RA.10

This study does have some important limitations. As an

observational study, it cannot uncover the molecular or

biologic pathways linking exposure to cigarette smoke and

the development of RA but can only point to interesting

associations that should lead to further research. Only 7% of

self-reported incident cases of RA were confirmed in this

cohort. We have very stringent case-validation procedures

that may have led to the exclusion of some RA cases but

ensured high specificity of case classification. All uncon-

firmed RA and other CTD cases were excluded from theanalyses. Given that all prevalent cases diagnosed before the

start of the cohort were excluded, the 0.8% prevalence rate

for new RA cases diagnosed after 1976 when women were

aged 30 to 55 years is in line with the expected 1% to 2%

prevalence rate of RA expected in a mainly white adult

female population.1,22 We have also analyzed the charac-

teristics of nonresponders to our supplemental questionnaire

(CSQ) and request for medical records, and they do not

seem to be different from those of the responders. The riskof RA was equally elevated in past and former smokers and,

in our lagged analyses censoring follow-up at the onset of

symptoms and at 2 years before RA diagnosis, the results

were unchanged, suggesting no effect of early RA symp-

toms on smoking behaviors.

The presence of RF was not assessed in a standardized

fashion. Rather, RF tests were performed in many different

laboratories and reported in medical records that were then

reviewed for the presence of ACR criteria. The development

of RF seropositivity may have been missed if only checked

once in early RA, and thus a few cases of seropositive RA

may have been misclassified as RF negative. In addition, weexcluded subjects at the first report of any cancer other than

skin cancer, believing that the development of a malignancy

was likely to influence smoking behavior. In doing so,

however, we may have been excluding those subjects who

were the heaviest smokers, potentially at the highest risk of

developing RA, biasing our findings. In our sensitivity anal-

ysis, including women who had previously developed can-

cer, we found that the overall risk of RA was unchanged.

As a prospective study with exposure information col-

lected before the development of incident RA and smoking

information updated every 2 years, our study has the ad-

vantage of eliminating the biases that can occur in case-

control studies, and reemphasizes that heavy cigarette

smoking is an important risk factor for RA in women and

that this risk is proportional to both the daily amount and

number of years of smoking. The risk of RA remains ele-

vated long after cessation of smoking, and adjustments for

age, socioeconomic status, body mass index, and known

reproductive risk factors have only minor influences on the

risk of RA, suggesting that cigarette smoking acts through

an independent pathway. Unfortunately, the prevalence of

smoking among young women in this country has grown in

recent years.

31

One quarter of the 680 new cases of RAdiagnosed after the age of 35 years in this cohort could have

been prevented if none of these women had ever smoked.

Our findings add to the long list of known health hazards

posed by cigarette smoking and to the reasons that young

women should be dissuaded from starting and encouraged

to quit smoking cigarettes.

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