National Public Health Institute, Helsinki and 1 Social Insurance Institution and National Public Health Institute, Turku, Finland.
Correspondence to: T. Korpilähde, Tammelantie 43, 97220 Sinettä, Finland. E-mail: tuula.korpilahde{at}fimnet.fi
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Abstract |
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Methods. A total of 6947 men and women aged 30 yr or over and free of clinical arthritis were included in the Mini-Finland Health Survey carried out between 1978 and 1980. Detailed histories of smoking and RF (sensitized sheep cell agglutination test) were obtained in the basic examination. In 2000, serum cotinine and thiocyanate were determined from serum samples collected at baseline and stored at 20°C. A cut-off point of 100 µg/l was used for serum cotinine and 10 µmol/l for thiocyanate to indicate active smoking.
Results. There was a close association between smoking and strongly positive RF. After adjustment for age, sex, coffee consumption and region, the odds ratios (95% confidence intervals in brackets) in current smokers and in those who had quit smoking were 3.94 (2.047.61) and 2.71 (1.335.53), respectively, compared with those who had never smoked. Among current smokers, the intensity, duration or tertiles of pack-years of smoking were not related to RF. No relationship between serum cotinine or thiocyanate and RF positivity was observed within the subgroups of current smokers and those who had quit. Among those who reported that they had never smoked but who nevertheless had serum cotinine levels at least 100 µg/l, the adjusted odds ratio of strongly positive RF was 4.48 (1.4813.50) compared with people who had never smoked and whose serum cotinine levels were less than 100 µg/l.
Conclusions. The results are not in line with the hypothesis of a doseresponse relationship between smoking exposure and RF positivity.
KEY WORDS: Cotinine, Rheumatoid factor, Smoking
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Introduction |
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The validity of self-reported smoking has been amply demonstrated. People may either over- or under-estimate the number of cigarettes they smoke daily, and the whole of their smoking history relies on memory. In addition, the amount of smoke products actually inhaled and absorbed tends to vary. Nicotine intake per cigarette ranges from 0.3 to 3.0 mg, depending on how cigarettes are smoked. Thus, self-reported measures in smokers, such as cigarettes smoked per day, are highly imprecise [14]. Black people are often reported to smoke fewer cigarettes per day, but still show higher levels of serum cotinine, which is the major plasma metabolite of nicotine. The underlying reason may lie in differing metabolism of cotinine or in higher intake of nicotine per cigarette by deeper inhalation among black people [15]. Although self-reported smoking status in Finland was concluded to be quite valid based on comparisons with serum cotinine levels [16], the possibility of recall bias remains and thus misclassification is possible.
Currently serum cotinine concentration is regarded as the best biomarker available for detection of exposure to tobacco smoke and for discriminating active smokers from non-smokers. A mean of 7080% of nicotine is converted to cotinine, which has a half-life of about 17 h [14]. The cut-off points mostly used for serum cotinine in separating active smokers from non-smokers are between 100 and 200 µg/l [16]; active smokers usually have serum levels higher than 15 µg/l [17]. Passive smoking usually has only a slight effect on cotinine level. Yet some overlapping may exist between non-smokers highly exposed to environmental tobacco smoke and occasional smokers or those who inhale very little smoke [17]. Those non-smokers who are exposed to typical levels of environmental tobacco smoke have cotinine levels below 1 µg/l, whereas heavy exposure to environmental tobacco smoke produces cotinine levels up to 15 µg/l [17]. Another biomarker of tobacco exposure is serum thiocyanate; it is less specific than cotinine, but its advantage lies in its long half-life of about 7 days [18].
The close association between smoking and RF was previously established in the Mini-Finland Health Survey [7]. In the present study we re-analysed the association using more detailed information on intensity and duration of smoking and on the type of tobacco smoked. The cotinine and thiocyanate concentrations were determined from stored serum samples to estimate exposure to tobacco smoke. The main aim was to evaluate the doseresponse relationship between smoking and RF.
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Material and methods |
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In the present study, subjects with arthritis were excluded from the analyses. Arthritis was diagnosed based on medical history, symptoms, physical examination and hand radiographs. The methods and diagnostic criteria used for evaluating the presence of arthritides have been described in detail elsewhere [19].
The sensitized sheep cell agglutination (WaalerRose) test was performed by the time of the baseline survey for 6947 men and women free of arthritis. The test was carried out on microtitre plates, as described elsewhere [7, 19]. Titres 32 were regarded as positive and titres
128 as strongly positive. In 2000, serum cotinine and thiocyanate were determined from serum samples that had been stored at 20°C. The serum cotinine concentrations were determined with a method employing a modification of the Nicotine Metabolite radioimmunoassay kit (Diagnostic Products Corporation, Los Angeles, CA, USA) [20]. For serum cotinine a cut-off point of 100 µg/l was used to separate smokers from non-smokers [16]. The serum thiocyanate concentrations were determined colorimetrically, using ferric nitrate to generate ferric thiocyanate [21].
Smoking history was elicited using the following questions:
Pack-years of smoking were computed for current smokers. One pack-year was regarded as equivalent to 20 cigarettes smoked daily for 1 yr. A person who had smoked at least one cigarette, cigar or pipe daily for at least 1 yr was regarded as a current smoker. An ex-smoker had stopped smoking at least 1 month earlier.
The logistic regression model was used to estimate the strength of associations between smoking and false-positive RF reactions [22]; adjusted odds ratios with 95% confidence intervals were based on the model. Previous studies based on the Mini-Finland Health Survey have demonstrated regional differences in the prevalence of RF [23] and a linear relation between coffee consumption and RF [24]. Since geographical region and coffee consumption are also known to be associated with smoking habits, these factors were entered into the models as potential confounding factors in addition to age and sex. Effect modification was examined by also entering interaction terms into the models. The statistical significance of the interactions was tested, using the likelihood ratio test and expressed as P values.
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Results |
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Discussion |
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The subjects who reported that they had never smoked but whose serum cotinine still indicated active smoking showed a 4-fold risk of developing strongly positive RF. In men, smoking of pipe or cigars in addition to cigarettes appeared to be most strongly associated with RF. These findings were based on a few cases only and thus should be interpreted cautiously.
In the absence of arthritis the prevalence of strongly positive RF was 1.0%. Previously, Tuomi et al. [7] reported that false-positive RFs occur about twice as often among current and past smokers than among those who never smoked. In addition, they showed the proportion of smokers to increase with increasing RF titre, so that the prevalence of high titres (WaalerRose 500) was 4-fold among current smokers and 2-fold among ex-smokers. Jónsson et al. [6] reported an association between active smoking and combined elevation of IgM and IgA RF that was more persistent among smokers than non-smokers. In our study we found a close association between smoking and strongly positive RF among current smokers and a modest association among ex-smokers; these results are in agreement with previous studies [6, 7].
An interesting detail was noted among those who reported that they had never smoked but still had serum cotinine levels of at least 100 µg/l: an increased prevalence of RF positivity. Since heavy environmental exposure to tobacco smoke usually produces serum cotinine levels up to 15 µg/l [17], those subjects have obviously misrepresented their smoking status and actually been smokers. Rebagliato [17] has summarized 11 studies in which self-reported smoking status was compared with serum cotinine measurements and noted misclassification rates from 0.9 to 9.8%. Recall bias is also possible in our study because it relies on memory, yet it should be very easy to remember never having been a smoker. Although our finding was based on only four cases, it may support the hypothesis of a causal relationship between smoking and positive RF.
Serum thiocyanate showed no association with RF in any category of smoking history. It is less specific than serum cotinine as an indicator of active smoking, which may explain why it showed no association with RF in those who had never smoked.
It seemed contradictory that serum cotinine concentration was associated with RF among never smokers but not among ex-smokers. This may be due to the sharper comparison contrast between low and higher levels of serum cotinine among never smokers, because ex-smokers in this study had an almost three-fold risk of having strongly positive RF compared with those who reported as having never smoked.
The time elapsed since smoking appeared inversely proportional to the prevalence of RF among ex-smokers. The result is in parallel with a prospective cohort study concerning RA-associated RF in post-menopausal women [25] which showed that women who had quit smoking more than 10 yr before the study were no longer at increased risk of developing RA.
We found no association between intensity of smoking, duration of smoking and tertiles of pack-years smoked with RF positivity. These results are not in agreement with other recent studies on RA; the study mentioned above concerning post-menopausal women found both intensity and duration of smoking to be associated with RA [25]. Another retrospective cohort study concerning only women found duration, but not intensity, of cigarette smoking to be associated with a modestly increased risk of developing RA [26]. A population-based casecontrol study, using incident cases, found increased risk of developing RA after a long duration but merely with a moderate intensity of smoking and the risk remained for several years after smoking cessation [9]. A retrospective casecontrol study done in Sweden found smoking at any time to be associated with RA in both sexes. In men, an increase in risk was found with increasing pack-years smoked [11]. A casecontrol study done in the UK found an increasing association between increased pack-years smoked and RA [10], in which the risk of developing RA was 6-fold after 3140 pack-years and 14-fold after 4150 pack-years smoked. Thus, our results are not in line with the hypothesis of the association between cumulative exposure to tobacco smoke and RF positivity.
Instead of focusing on the association between smoking and RA, we focused on the strongly positive RF reaction sometimes occurring in non-rheumatoid subjects, which can precede clinical disease by years [1]. The study was representative for the Finnish population and the participation rate was high (90%). Recall bias is possible, because smoking history relies on memory. Yet we used serum cotinine and thiocyanate to discriminate active smokers from non-smokers and to quantify the exposure to tobacco smoke.
Newer RF determination methods were not used in the present study because RF had been measured at the baseline survey and at that time the sensitized sheep cell agglutination test was the method of choice. Previous studies focused on RF from the Mini-Finland Health Survey have been based on this method [7, 23, 24].
Cotinine and thiocyanate are stable compounds. In the present study their serum concentrations made a good distinction between never smokers and ex-smokers and current smokers. Thus, the serum determinations can be considered accurate.
It should be emphasized that although the doseresponse relationship is lacking from our results, its absence does not imply falsification of the possible causation between smoking and RF positivity [27]. Biological plausibility is difficult to clarify, because the mechanisms governing how smoking may influence the immune system, leading to increased production of RF, remain unknown. The analogy can be tested; the number of cases of seropositive RA may increase among young women in the future due to the increase in smoking seen among young girls today.
Smoking continues having high interest as a risk factor for RF-positive RA. However, surrogate measures of smoking were not explored in previous studies. A limitation of the present study is that although it comprised almost 7000 participants, some of the findings were based on low numbers of cases. Thus, we cannot exclude the possibility that insufficient sample size and variation in the indicators of intensity and duration of smoking may explain the absence of a doseresponse relationship between smoking and RF in this study. Due to the increased mortality related to smoking and RF, furthermore, a survivor effect may remain in a cross-sectional study like the current one.
In summary, the present study shows a close association between smoking and strongly positive RF. Yet, the results are not in line with the hypothesis of a doseresponse relationship between smoking exposure and RF positivity.
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The authors have declared no conflicts of interest.
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References |
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