Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons. Although its etiology remains unknown, certain environmental (non-genetic) factors have been postulated as potential causative factors[1]. Cigarette smoking, in particular, has attracted interest as a risk factor for ALS. Smoking could increase the risk of ALS through several mechanisms, including inflammation, oxidative stress, and neurotoxicity caused by heavy metals and other chemical compounds present in cigarette smoke[2–5].

A number of epidemiologic studies have assessed the association of cigarette smoking with ALS incidence, but their results have been inconsistent[6]. More recently, a systematic review and meta-analysis has suggested that sex could modify the association between smoking and ALS risk, with smoking linked to higher risk of ALS in women but not in men[7]. Similarly, the only three studies that estimated the association of smoking with the survival of ALS patients were inconclusive[8–10].

Here we present estimates of the association of smoking with ALS risk, and with survival in ALS patients, in the General Practice Research Database (GPRD), a large clinical database in the United Kingdom (UK).

Results were similar when we included only cases and controls with at least five years of follow-up before their index date (table 2), when we adjusted for body mass index (data not shown), and when we excluded individuals older than 75 on the index date: the RR (95% CI) was 0.77 (0.52-1.15) in men and 1.50 (0.96-2.35) in women. The RRs of ALS for heavy smokers and non-heavy smokers were of similar magnitude compared with never smokers. The RR (95% CI) of ALS in heavy smokers compared with never smokers was 1.08 (0.74-1.56) in the entire cohort, 0.72 (0.44-1.19) in men and 1.77 (1.02-3.09) in women. The corresponding figures comparing non heavy smokers with never smokers were 1.03 (0.80-1.33), 0.75 (0.53-1.06) and 1.50 (1.02-2.21).

Of 1131 ALS cases with at least one day of follow-up after their diagnosis, 802 (70.9%) died, 108 (9.6%) transferred out, and 221 (19.5%) were alive at the time of last recording in the GPRD, after an average follow-up of 2.1 years. Median survival after diagnosis was 1.5 years. Old age and female gender were strongly associated with mortality. Each 5-year increment in age was associated with 20% higher mortality rate (RR 1.20, 95% CI, 1.16-1.24). Similarly, women had a 22% higher mortality than men (RR 1.22, 95% CI, 1.06-1.41). Compared with never smokers, the mortality RR (95% CI) was 1.45 (1.03-2.03) for heavy smokers and close to 1 for all other groups (table 3). Compared with never smokers, the mortality RR (95% CI) for ever smokers was 1.31 (1.04-1.65) in women and 0.90 (0.72-1.11) in men. The risk was particularly elevated in female heavy smokers (HR 1.94, 95% CI 1.24-3.06). As shown in figure 1, adjusted survival was lower in women who were ever smokers compared to men and women never smokers. Results were similar when we excluded individuals diagnosed with an ALS variant.

In this large prospective study, smoking was a predictor or ALS in women, and of mortality in female ALS patients, but not in men.

Smoking has been associated with several neurodegenerative disorders. Prospective investigations have found a higher risk of dementia and a lower risk of Parkinson's disease in smokers compared to non-smokers[20, 21]. The epidemiologic evidence regarding smoking and ALS is less consistent, with some studies showing a higher risk of ALS among smokers,[22–24] and others not finding any clear association[25]. Notably, in the Cancer Prevention Study II cohort, a prospective cohort including over 1 million people, results were similar to ours: ever smoking was associated with a higher risk of ALS mortality in women (HR 1.32, 95% CI 1.03-1.69) but with a lower risk in men (HR 0.77, 95% CI 0.59-1.00)[26]. Consistent with this observation, a recent systematic review and meta-analysis showed that the proportion of men and women in a particular study made a major contribution to between-study heterogeneity[7]. The estimated pooled RR of ALS in ever versus never smokers was 0.87 (95% CI 0.71-1.06) in men, and 1.58 (95% CI 1.21-2.08) in women[7]. Results from the GPRD are in agreement with the previous meta-analysis and reinforce its conclusions.

Smoking could increase the risk of ALS through different mechanisms. Strong evidence supports the role of smoking as a cause of oxidative damage,[2] and oxidative damage has been involved in the pathogenesis of ALS[27]. Also, more than 4 thousand different compounds have been identified in tobacco and cigarette smoke, including heavy metals, such as lead or cadmium, and formaldehyde[28]. Although the role of these in ALS pathogenesis has not been defined, some studies point to an increased risk of ALS and worse ALS survival associated with higher levels of lead exposure,[8, 29] and to a potential higher incidence of ALS in individuals exposed to formaldehyde[30]. Systemic inflammation, another well-known effect of smoking, might also be involved[4]. Biological mechanisms supporting the difference in the association of smoking with ALS in the two genders are less clear, though prior observations suggest that women could be more sensitive to deleterious effects of cigarette smoking, probably through differences in the metabolism of tobacco compounds[31, 32]. Additional evidence suggests that the association of smoking with different health outcomes, including lung disease or thyroid disorders, might differ by gender[32, 33].

More intriguing is the sex difference in the association of smoking with survival. Only three previous studies have reported associations of smoking with ALS prognosis. Kamel et al studied the association of different exposures, including smoking, with survival in a group of 100 ALS cases in New England. In age and sex-adjusted analysis, ever smokers had a better survival than never smokers (HR 0.6, 95% CI 0.4-1.0, with time from diagnosis to death as the outcome, or HR 0.7, 95% CI 0.5-1.2, with time from onset of symptoms to death as outcome)[8]. In a report including 180 ALS patients from Washington State, smoking did not predict mortality: compared to never smokers, the HR of death in current smokers was 1.1 (95% 0.7-1.6) and 1.0 (95% CI 0.7-1.4) in past smokers[9]. Neither study assessed the association separately in men and women. Finally, smoking was not a significant predictor of survival in a group of 2069 ALS patients receiving riluzole in France, but the actual estimates of association were not reported[10].

Strengths of our study include the large sample size, providing enough statistical power for subgroup analysis, and the selection of cases and controls from a well-defined cohort, reducing the possibility of selection bias. Several limitations, however, might reduce the validity of our results. First, we have not confirmed all ALS cases identified in the GPRD, though a previous study suggested acceptable validity of the computer diagnosis[17]. Because validity of ALS diagnosis could be lower in older individuals,[34] we repeated analyses after excluding those older than 75, obtaining similar results. Second, smoking status was classified in broad categories (never, non-heavy smokers, heavy smokers, unknown). Thus, we were not able to determine precise dose-response relationships. Lastly, unmeasured confounding could explain our results if a risk factor for ALS was associated with smoking and distributed unevenly in men and women.

We have found that smoking is associated with higher risk of ALS and worse survival in women but not in men. Future studies should focus on exploring the mechanisms that might explain the observed associations.