Relationship Between Smoking and Patient-reported Measures of Disease Outcome in Ankylosing Spondylitis

MATERIALS AND METHODS

Between April and July 2007, 1000 patients with AS from 10 secondary care rheumatology centers across the UK (Abergavenny, Bristol, Cambridge, Cannock, Glasgow, Kent, Lancaster, Newcastle-upon-Tyne, Stoke-on-Trent, Torbay) were invited by their consultant rheumatologist to take part in a postal survey consisting of a questionnaire that incorporated both generic and disease-specific patient-reported outcome measures (PROM). The centers were specifically chosen to encompass areas of differing socioeconomic status and geographic populations. Eight of the centers were situated across England, 1 was located in Wales and 1 in Scotland; there were about equal numbers of participants invited from each center.

The North Staffordshire Local Research Ethics Committee and the 10 site-specific National Health Service trusts approved the multicenter cross-sectional study. The main aim of our study was to evaluate EASi-QoL²¹. Three surveys were carried out: at baseline, 2 weeks, and 6 months. Data collected from the baseline survey are reported in our study.

Patients invited to take part in the survey were over 18 years of age, had AS according to the modified New York criteria (1984)²², and provided written informed consent according to the Declaration of Helsinki. Those with the inability to comprehend English and those with learning difficulties were excluded from the study.

RESULTS

Of the 1000 participants invited, 612 completed the questionnaire. After taking into account deaths and changes of address (n = 44), the adjusted response rate was 64%. Of these, 606 provided information on smoking history. The characteristics of the patients are shown in Table 1.

A history of smoking (past and current) was found in 49.2% of patients, with 21.0% currently smoking. The vast majority of smokers (93.3%) started smoking before disease diagnosis. There was no significant difference in age or disease duration between nonsmokers and current smokers (49.2 vs 49.2 yrs and 16.5 vs 14.6 yrs, respectively), but past smokers were significantly older and had a longer disease duration (54.8 and 20.6 yrs, respectively) than nonsmokers or current smokers (p < 0.0001). Patients with a history of smoking were more likely to be men than women, although the difference did not achieve significance (51.4% vs 44.0%; OR 1.34, 95% CI 0.93–1.95, p = 0.1). Male smokers had smoked more pack-years than female smokers (23.1 vs 17.1; p = 0.04), and current smokers were also more likely to be male than female (23.3% vs 14.9%; 95% CI 1.05–2.89, p = 0.02). Current smokers had a greater pack-year history than past smokers (23.0 vs 20.7; p = 0.04).

DISCUSSION

This is the largest study conducted to date examining the2quantitative effect of smoking in patients with AS. The results provide substantial evidence of a negative effect of smoking on disease activity, pain, function, and quality of life, which is consistent with the findings from previous, smaller studies that have been conducted in AS populations^{5,6,7,8,9,10,11,12}. For the first time, we also report a dose-dependent relationship between smoking and outcome measures in patients with AS, and show that this is independent of socioeconomic status. These findings suggest that smoking is unlikely to be just a surrogate of another lifestyle factor or some other health behavior, a suggestion that has been made in previous studies^5,9,10.

The observed dose-dependent relationship could be due to the cumulative effects of smoking, such as increased levels of inflammation and/or a direct effect on the musculoskeletal system. Another possibility is that smoking may interfere with certain treatments used in AS. Recent studies involving patients with RA have shown that smoking is associated with an increased lack of response to treatment with tumor necrosis factor (TNF) antagonists^{24,25,30,31,32}. Although anti-TNF is also used in AS, relatively few patients in this cohort were treated in this way (11.6%), so it is unlikely that this could explain the effect of smoking in this group. However, it has been shown that smoking also adversely affects the response to methotrexate in RA^32,33, and that smokers with RA have a greater need for disease-modifying antirheumatic drugs and feel worse than nonsmokers, without having more joint damage³⁴. Thus, there may be a more general effect of smoking on therapies that are used in the inflammatory arthritides.

We found that BASDAI scores were higher in smokers than in those who had never smoked. Although an increasing BASDAI score was seen with increasing pack-year history, multivariate analysis suggested that the strongest association was with current smoking, which is consistent with a previous study¹⁰. Similarly, an increased level of pain was seen in current smokers compared to past smokers or those who had never smoked, and multivariate analysis suggested that pain was primarily associated with current smoking rather than pack-year history. However, it is difficult to distinguish between the effect of current smoking and the cumulative effects of longterm smoking, especially since current smokers had a greater number of pack-years than past smokers. Further, the association with pack-years is not straightforward, since patients with up to 15 pack-years appeared to be no worse in terms of pain or disease activity than patients who had never smoked. However, further increases in pack-years, especially beyond 30 pack-years, were associated with significantly higher levels of pain and disease activity.

This is, to our knowledge, the first study to examine the relationship between smoking and pain in patients with AS, although previous studies have reported greater levels of pain in smokers with other musculoskeletal disorders^35,36,37,38. It has been postulated that this relationship might arise from effects on neurological processing of sensory information, or by damage to musculoskeletal tissues through vasoconstriction, hypoxia, etc.³⁸. Alternatively, smokers may demonstrate neuropsychological or sociocultural differences that are reflected by differences in personality or illness behavior; these may include a lower threshold for reporting pain and disability³⁸.

Apart from 1 small study²⁰, our finding that smoking was associated with worse functional ability is consistent with other studies^5,6,7,8,9,10. However, we have shown that there is a dose-dependent effect of smoking, and that this is independent of age, sex, disease duration, and social deprivation. It is unclear why 2 other studies found an association with current smoking but failed to find a relationship with pack-years^9,10. However, these were smaller studies than ours, so possible associations may have failed to reach significance. Further, no information was provided on the pack-year history in these patient cohorts, so it is possible that differences may be explained by differences in the intensity levels of smoking in different AS populations.

There are many possible mechanisms by which smoking may result in decreased function. An increase in comorbidity and a reduction in physical activity in smokers are likely factors. Smoking may also add to the already poor lung function of these patients, which further decreases their functional ability. Kaan and Ferda⁶ found that smokers with AS had reduced vital lung capacity compared to nonsmokers, but were unsure whether this was due to parenchymal damage or to additional fusion of joints in the thorax, causing restriction. A further possibility is that smoking causes increased inflammation in joints, leading to reduced mobility. Two previous studies have found that smokers had worse results for Schober’s test, finger-to-floor distance, and occiput-wall distance^6,7, findings that suggest smokers have a reduced range of motion that could lead to reduced function.

Quality of life was also shown to be significantly worse in those who had ever smoked compared to those who had never smoked, as measured by ASQoL and all 4 domains of EASi-QoL. In the latter case, pack-year history appeared to be more strongly associated with these measures than current smoking. This is possibly related to increased disease activity and reduced functioning of patients with AS who smoke. Apart from an effect on disease activity, smoking is likely to have a cumulative effect on cardiac and pulmonary systems, which would lead to lower scores on ASQoL and EASi-QoL. Smoking is also known to be a risk factor for peripheral vascular disease and osteoporosis, which may affect a patient’s quality of life.

The increasing severity of outcome measures with increasing pack-year history suggests that cessation of smoking in patients with AS may be beneficial. However, the benefit derived may depend on the amount of damage already accumulated. This is likely to depend on a number of factors, including length of time smoked, number of cigarettes, duration of disease, and age when cessation occurs. Stopping smoking may reduce the chance of further harmful effects, but it is unclear whether accumulated damage can be reversed and whether benefits of smoking cessation are dependent on the length of the cessation. In a cross-sectional study such as ours, it was not possible to directly address the effect of smoking cessation on disease measures, and longterm, prospective studies monitoring the progress of smokers who had quit would be needed to address this question.

Our study has various strengths, including a large sample size, use of multiple centers across the UK, and the use of validated AS-specific outcome measures, which make the results more reliable than some studies conducted to date. However, there are also several limitations. First, information was not obtained on patients failing to respond to the questionnaire, so it was not possible to determine whether there were differences in smoking status or socioeconomic background between participants and nonparticipants. However, the centers chosen were in regions that provided a diverse socioeconomic and geographic population by covering both urban and rural areas across the UK. We therefore believe that our results represent those from a typical population of patients with established AS.

Another possible limitation may relate to the use of PROM, which are subjective measures of disease outcome and may therefore be open to misinterpretation. Third, the use of pack-years as a quantitative measure of smoking may be subject to some inaccuracy due to recall bias or difficulty in accounting for variation in the number of cigarettes smoked by participants over their lifetime. However, by categorizing smokers into 3 broad groups according to pack-year history, we believe that, in a large study such as this, it is possible to get a reasonable estimate of the association with different levels of smoking. Finally, the data were collected at baseline in a cross-sectional study. Cross-sectional studies, although valuable when looking at associations, cannot assess causation. It is possible that patients may have started smoking or smoked more because of more severe disease (reverse causality). However, the vast majority of patients (> 93%) had started smoking long before development of disease (median 15 years), and 57% of smokers had stopped by the time of the study. Further, in those who had stopped smoking, there were still significant dose-dependent associations between previous pack-year history and current outcome measures (data not shown).

Overall, the results of our study strongly support smoking cessation in patients with AS and advocate that more should be done to encourage these patients to quit, or at the very least to attempt to reduce the number of cigarettes they smoke. This could be achieved by promoting specialist smoking cessation clinics and providing more information during clinic appointments about the negative effects of smoking.