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Does Smoking Influence Disease Outcome in Patients with Rheumatoid Arthritis?

Cigarette smoking has been recognized to be an important etiological factor in lung cancer and cardiovascular disease for many years. However, it is only recently that smoking has been studied as a possible cause of rheumatoid arthritis (RA). There is now consistent evidence from several epidemiological studies that smoking is a risk factor for developing RA, particularly in men. These data have been reviewed in The Journal^1,2.

The underlying mechanisms for the association between smoking and RA are unknown, but may be due (1) to a direct biological effect of cigarette smoking, or (2) to confounding. In support of the former, studies of patients with RA have shown that smokers are significantly more likely to be rheumatoid factor (RF) positive^3,4. Further, in population studies of individuals without RA, smoking is also associated with RF production⁵. It is therefore possible that smoking predisposes to RA by inducing RF. An extension to this hypothesis, given that RF is an important predictor of severe RA, is whether smokers with RA have worse outcomes. This question was addressed by Dr. Wolfe in a study reported in this issue⁶.

In this carefully conducted cross sectional study, Wolfe examined the influence of cigarette smoking on disease outcome and RF positivity among 640 patients with RA seen at the Arthritis Center in Wichita between 1991 and 1997. The mean duration of disease was 14 years and 81% were RF positive. A smoking history was obtained at interview of: (1) smoking status (current/past/never); (2) number of years of smoking; and (3) number of packs smoked per day. Disease outcome was assessed at the most recent clinic visit using a tender joint count, erythrocyte sedimentation rate (ESR), visual analog pain score, Health Assessment Questionnaire (HAQ) score for functional disability, Arthritis Impact Measurement Scale (AIMS) anxiety and depression score, and Larsen score for radiological damage on hand radiographs. Of 640 patients, 18% were current smokers, 28% ex-smokers, and 54% had never smoked. As expected, cigarette smoking was more common in males. Wolfe found that smokers were more likely to be RF positive, with higher titers in those who had smoked longer, especially males. Rheumatoid nodules were also more common in smokers, even after adjusting for the effect of RF. Although Larsen scores for radiological damage were not influenced by smoking status in ever smokers, higher Larsen scores were found in those who had smoked longer, after adjusting for age and disease duration. The relationship, however, was nonlinear, and confined to those patients who had smoked more than 20 years. This association remained even after controlling for RF. There was no effect of smoking on tender joint count, ESR, levels of anxiety and depression, pain, or HAQ score. Wolfe concludes that smokers of long duration have more severe disease, in terms of radiological damage, but not more active disease, in terms of tender joint count, pain score, and ESR. Perhaps surprisingly, the influence of smoking in current was similar to ex-smokers.

Wolfe refers to the recent report by Saag, et al, which also investigated the influence of smoking on disease outcome in RA³. In that study of 336 patients with established RA attending a university clinic in Iowa, USA, it was reported that smokers were more likely to develop radiological erosions. However, in contrast to the results of Wolfe, the relationship disappeared when controlling for RF, suggesting that the higher frequency of erosions in smokers was directly related to a higher prevalence of RF. In addition, Saag, et al only found an association between smoking and the Larsen score at low levels of radiological damage, and therefore suggested that smoking was responsible for the initiation rather than the severity of erosions. In two smaller studies, 59 and 41 patients with established RA, respectively^7,8, no association between smoking and the Larsen score was found.

There are methodological issues in such cross sectional studies, with restriction of inclusion to patients with prevalent disease. A particular concern is that disease severity may influence smoking habits, which may lead to a false association between smoking and more severe disease in cross sectional studies. A more accurate picture would be gained by studying the effect of smoking on disease outcome among patients followed prospectively, with ascertainment of smoking status close to disease onset. It would also be interesting to compare the effect of comorbidities and response to disease modifying antirheumatic drugs in smokers and nonsmokers, both of which may influence disease outcome.

The available data are nonetheless consistent: smokers are more likely to be RF positive and to develop rheumatoid nodules^3,5. However, the evidence is still conflicting as to whether, after allowing for a higher frequency of RF, smokers have higher levels of radiological damage^3,6–8. It is also unclear how smoking might exert such an effect. One possible path is that, given that persistent joint inflammation leads to joint damage, it could be argued that if smokers have higher levels of inflammation, this might increase radiographic damage. However, this does not appear to be the case. Despite reporting higher Larsen scores in patients who had smoked for more than 20 years, Wolfe found no effect of smoking on the tender joint count, ESR, or HAQ score⁶. Similarly, others have reported that smokers and nonsmokers had broadly similar HAQ scores^7–10, disease activity scores^8,10, and C-reactive protein¹⁰.

Smoking does influence the immune system, in part by effects on sex hormones. It is unclear, though, whether smoking would be expected to increase or decrease joint inflammation. Thus smokers have been found to have abnormalities in T lymphocytes, and reduced levels of natural killer cells and antigen-presenting cells^11,12. The effect of hormonal changes in smokers is also complex, and is likely to differ between males and females. Smokers have higher levels of androgens, which are immunosuppressive¹³. By contrast, smoking is "anti-estrogenic"¹⁴, which may enhance the immune response since estrogens suppress cell mediated immunity. It is also interesting to note the disease suppressive effect of smoking on other inflammatory conditions such as inflammatory bowel disease¹⁵.

The association between smoking and disease outcome may be indirect. The literature on smoking and osteoarthritis (OA) is interesting, but argues against a deleterious effect of smoking, as the latter protects against the development and severity of OA¹⁶. A possible explanation for this is that smokers tend to be thinner and less physically active, thereby exerting less stress on their joints. A similar mechanism may underlie the observation by Wolfe and Zwillich that smokers with RA were less likely to require total joint arthroplasty¹⁷.

One major consideration is that cardiovascular disease is still reported to be the commonest cause of death in RA¹⁸. Further, vasculitis, which is commoner in smokers¹⁹, has a high risk of mortality. Thus although we do not yet fully understand the effect of smoking on RA, we agree with others that there are plenty of other important reasons for patients with RA to quit the habit²⁰!

BEVERLEY J. HARRISON, MD,
Department of Rheumatology,
Withington Hospital, Manchester M20 2LR;

ALAN J. SILMAN, MD,
ARC Epidemiology Unit,
University of Manchester,
Stopford Building, Oxford Road,
Manchester M13 9PT, UK.
Address reprint requests to Dr. Silman.

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