Rheumatoid arthritis (RA) is a long-term autoimmune disease which is thought to be related with genetic and environmental risk factors. One of the few modifiable risk factors is smoking. The relationship between smoking and RA has been shown in a lot of studies and reviews previously. The first study that related smoking with an increased risk of developing RA was published in 1987,1 and since then, numerous additional studies have been reported. Most of these studies were completed 10 or more years ago, and both the diagnosis and treatment/s available for RA have changed substantially in the last decade. Additionally, the routine collection of health data for research has now enabled the conduction of bigger studies in actual practice conditions and using the entire population, in contrast with previous cohorts or case–control studies mostly conducted in specialised research centres.2 Finally, none of the studies published to date were conducted in Mediterranean populations, where both the incidence/prevalence and the severity of RA are lower than in Northern European and American people.3,4

We therefore took advantage of the existence of routinely collected health data from electronic primary care records in Catalonia (Spain) to study the association between smoking and the development of rheumatoid arthritis in the general population.

In total, we included 13,920 RA cases matched to 69,535 controls with a similar age, gender and same primary care practice. Average (standard deviation) age was therefore similar between cases (64.67±15.67 years) and controls (64.04±15.83), and the proportion of females was the same in both groups (70.42%). In addition, body mass index was also similar between cases and controls, and the prevalence of co-morbidity was also comparable, except for inflammatory bowel disease, peripheral artery disease and pulmonary embolism, all three being more common amongst RA cases. Detailed baseline characteristics for cases and controls are reported in Table 1.

Before imputation, a total of 2227/13,920 (16.9%) of RA cases were current smokers, compared to 7637/69,535 (13.45%) controls, and remained similar after imputation (see Table 1). Unadjusted (sex, age, and GP-matched) OR for RA in ex-smokers was 1.09 [95% CI 1.03–1.14] and 1.35 [1.28–1.43] for current smokers. Multivariable adjusted ORs were 1.19 [1.12–1.26] and 1.28 [1.20–1.37] respectively. In the pre-specified gender stratified analysis, the observed association was stronger in men, with an adjusted OR 1.38 [1.27–1.50] for current smokers, compared to women (adjusted OR 1.20 [1.09–1.32] for current smoking). Full results for these models are depicted in Fig. 1.

Fig. 1.

Multivariable adjusted ORs for the association between smoking and RA stratified by gender.

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To our knowledge, this is the largest and most up-to-date epidemiological study on the association between smoking and the development of RA to date. Our analysis is also the first to include a Mediterranean population, with previous studies conducted in Northern European,7 American,6 and Asian patients.8 Our study supports previous findings of an association between smoking and the risk of developing RA, with an almost 30% higher risk for current smokers and a 20% increase for ex-smokers compared to never smokers. In addition, we found a stronger effect of smoking amongst men, with an almost 40% excess risk in current smokers and a 15% in ex-smokers.

Our data do not differ from the results obtained in other studies done previously in different populations: most previous case–control studies found similar associations between current smoking and the risk of developing RA, with ORs ranging from 1.42 [1.13–1.80] to 2.37 [1.56–3.60].6,9 Similarly, cohort studies have mostly found an excess risk associated with smoking.10–12 Some controversial findings have however been published previously, that found no association between RA and smoking.13

Our study suggests that the effect of smoking on RA risk is long-lasting for years after smoking cessation, with ex-smokers still at an increased risk of developing RA compared to non-smokers. Interestingly, a recent study supports these findings: in a report by Seror et al.,14 passive smoking during childhood on the risk of developing RA.

Finally, other previous studies have shown3 like ours a stronger effect of smoking amongst men compared to women. It has been speculated that the observed difference in gender may be due to the difference in smoking intensity.3

One of the limitations of our study is the lack of detail on exposure intensity, i.e. cigarettes smoked per day or pack-years. Previous studies have reported on this, and found that smoking more than 20 pack-years make increase the possibilities of having RA.3 Also, with our data it is impossible to assess the timing when a person stopped smoking, and this makes ex-smoking effects difficult to interpret. An additional limitation is the use of routinely collected data, which was not designed for research purposes. Primary care coding of RA is likely delayed and/or focussed on more severe cases, as shown by the average age at diagnosis in our series, which is older than a recent study in Catalan population.15

On the other hand, our study has several strengths. This study includes the largest number of RA participants to date on this topic, with previous reports ranging from 90 to 7697 RA cases.12,16 Additionally, our study is the first one population-based, including all diagnosed cases of RA in a large population of around 6 million people, and in a Mediterranean region not previously studied. The diagnosis of RA has been previously validated in SIDIAP using laboratory and external rate comparisons.5 Finally, our controls were sampled from a universal primary care database making them representative of the general population. Matching on general practitioner minimised differences in socio-economic status, environmental factors, and physician differences in diagnostic or coding practices.

We confirm an association between smoking and the risk of developing RA. Research is needed on the impact of smoking cessation on the risk of developing this disease, and on related health outcomes including cardio-vascular disease and all-cause mortality in RA populations.

The research was partially supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). DPA is funded through an NIHR Senior Research Fellowship (Grant number SRF-2018-11-ST2-004). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health. APU is supported by Fundacion Alfonso Martin Escudero and the Medical Research Council (grant numbers MR/K501256/1, MR/N013468/1).

Dr. Prieto-Alhambra reports grants and other from AMGEN; grants, non-financial support and other from UCB Biopharma; grants from Les Laboratoires Servier, outside the submitted work; and Janssen, on behalf of IMI-funded EHDEN and EMIF consortiums, and Synapse Management Partners have supported training programmes organised by DPA's department and open for external participants. Mr Prats-Uribe reports grants from Fundación Alfonso Martin Escudero and the Medical Research Council. No other relationships or activities that could appear to have influenced the submitted work.