Background
Primary Sjögren’s syndrome (pSS) is an autoimmune disease primarily affecting the salivary and lacrimal glands, causing oral and ocular dryness. Other organs such as lungs, kidneys, nervous system, and skin may also be affected in the disease [
1]. pSS is associated with B-cell activation, presence of various autoantibodies, systemic symptoms and an increased risk of non-Hodgkin lymphoma [
2,
3]. The onset of the disease is often insidious and development of autoantibodies is seen years before onset of clinical disease [
4,
5].
The estimated prevalence varies widely. When using the American European consensus group criteria (AECG criteria) [
6] the prevalence of pSS is estimated to be between 11.3 and 236.1/100,000 in different European populations. Annual incidence estimates vary between 3.1 and 5.3/100000 [
7].
The aetiopathogenesis of pSS is poorly understood but it entails genetic factors [
8], hormonal factors [
9] and possible viral infections [
10], while environmental triggers are less well-studied. Smoking is a widely known risk factor for several malignant diseases [
11,
12], but also for chronic inflammatory disorders such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and Crohn’s disease [
13,
14]. Retrospective studies and studies with exposure measured before diagnosis [
15‐
17] in RA indicate that smoking is particularly associated with seropositive RA. In some diseases, such as ulcerative colitis, Behcet’s disease and Parkinson’s disease, smoking seems to have a protective effect [
18‐
20]. Only three studies have specifically addressed the association between smoking and pSS and in none of them has smoking been assessed prior to pSS diagnosis [
21‐
23].
The closeness of cigarette smoke to mucosal membranes and exocrine glands, and the effect of the cigarette smoke on the immune system, makes the influence of cigarette smoking on the development of pSS interesting. However, when studying associations with smoking, social status has to be taken into consideration because it can correlate with both smoking and other exposures such as environmental toxins and dietary factors. Finding epidemiological risk factors for pSS might help us understand the underlying pathogenesis and thus guide further studies. As smoking affects the development of several diseases, including rheumatic disease, we hypothesized that smoking also might affect the development of pSS. To our knowledge, this is the first nested case-control study on the relationship between smoking and socioeconomic status and subsequent diagnosis of pSS.
Discussion
In this study, being a current smoker was associated with a lower risk of later being diagnosed with pSS. Former smokers had a higher risk of subsequently being diagnosed with pSS, compared both to never smokers and current smokers. The same pattern is seen in ulcerative colitis [
18]. In Parkinson’s disease, there is also an inverse association between cigarette smoking and development of the disease [
20]. Interestingly, in three previous studies specifically addressing the association between smoking and pSS, there were fewer current smokers and more former smokers among pSS patients. The first study involved 355 pSS patients in whom there was a lower frequency of focal sialadenitis in lower lip biopsies and a lower frequency of anti-SSA positivity in patients with pSS who were smokers [
21]. However, as the Copenhagen criteria were used, in which the presence of anti-SSA/SSB or presence of focal sialadenitis are not mandatory, several patients not fulfilling the AECG criteria were included in that study. One interpretation of that study is that within a population of individuals with sicca symptoms, smoking is negatively associated with markers of autoimmune sialadenitis.
The second study was a cross-sectional study of 140 patients, fulfilling the AECG criteria, in which there were also more former smokers and fewer current smokers among patients with pSS [
22]. Finally, in a cross-sectional study of 207 pSS patients fulfilling the AECG criteria, there were fewer current smokers, but more former smokers compared to healthy controls [
23]. The characteristics of the patients in that study were similar to the characteristics after diagnosis of the pSS patients in the present study, except that they had a higher frequency of positive lip biopsies (99.5% compared to 85% in the present study). In three other studies, which investigated cardiovascular risk factors in patients with pSS, there were fewer current smokers in one study [
32], and in the other two studies there were fewer ever smokers [
33,
34], compared to controls. In the latter two, there was no information on the numbers of current and former smokers.
Smoking is shown to cause a short-term increase in salivary flow rate (SRF) but a long-term reduced SFR [
35,
36]. Cigarette smoking is also shown to cause ocular dryness when comparing chronic smokers with healthy controls [
37]. A potential explanation for the smaller numbers of current smokers and for the greater numbers of former smokers in cross-sectional studies of pSS is that oral and ocular dryness and pulmonary symptoms make the patients more prone to quit smoking, both due to dryness and the irritation caused by the smoke. Interestingly, in this study, cessation of smoking in the majority of pSS patients who were former smokers did not occur in close temporal proximity to symptom onset and the impact of smoking was similar in cases with a longer and shorter time to diagnosis, supporting the possibility that smoke cessation of smoking might not be a consequence of sicca symptoms. Instead, it may influence the development or progression of the disease. Still, we cannot exclude that very early dryness, occurring before the reported onset of symptoms, could influence the cessation of smoking.
Low levels of formal education and a poor socioeconomic status have been shown to predict a number of chronic disorders [
17,
26,
38,
39]. In contrast, in the present study, the level of education and socioeconomic status based on current occupation had no major impact on the risk of being diagnosed with pSS. This suggests that the observed negative association with smoking is probably not due to underlying exposures related to socioeconomic status, although we cannot exclude the possibility that other life style factors contribute to the development of pSS.
Cigarette smoke contains over four thousand different compounds [
40]. Nicotine is known to interact in the immune system and nicotine receptors are present on macrophages, T cells and B cells [
41‐
43]. Many other compounds in cigarette smoke can also affect the immune system [
44]. Several studies have shown that cigarette smoke has effects on the immune system, which reasonably could affect the development of different diseases. As cigarette smoke, among other things, is shown to affect neutrophils, macrophages, T cells, B cells, dendritic cells, and cytokine production (reviewed in [40 − 42]), it is hard to predict exactly how cigarette smoke might affect the development of pSS [
44‐
46]. One possible way is by inhibition of B cells: several studies have identified decreased levels of salivary IgA and decreased levels of serum IgG, and decreased levels of serum IgA and IgM and increased levels of IgE in smokers [
46]. Furthermore, significant increases in IgM and IgG in subjects who stop smoking have been reported [
47] and these changes seem to persist in former smokers for years after cessation of smoking [
48].
pSS is characterized by B-cell activation with high serum IgG-levels and a high frequency of autoantibodies such as RF, anti-SSA and anti-SSB [
1]. A reason why current smoking could be protective against pSS could be a suppressing effect of smoking on the B cells directly or by reduced production of B-cell activating factor [
49,
50]. In predisposed individuals who stop smoking, taking away the inhibitory effect of cigarette smoke on the B cells could lead to activation of autoreactive B cells that might trigger the development of the disease. The association between smoking and anti-citrullinated peptide antibody (ACPA)-positive RA, on the other hand, most likely reflects other mechanisms specifically related to RA, such as increased protein citrullination leading to early development of ACPA [
51].
As models of autoimmune diseases and the effect of cigarette smoking, inflammatory bowel diseases are interesting because smokers have a higher risk of Crohn’s disease but a lower risk of ulcerative colitis. Studies on ulcerative colitis and Crohn’s disease have identified distinct cytokine profiles, whereby Crohn’s disease is characterized by a T helper (Th)1 profile [
52,
53], while in ulcerative colitis a Th2 cytokine profile has been observed [
54,
55], with upregulated levels of IL-33 [
56]. IL-33 is a nuclear cytokine of the IL-1 family, which is constitutively expressed in epithelial barrier tissues and plays an important role in Th2 immunity [
57]. Recently, increased IL-33 in the salivary glands and in serum have been linked to pSS [
58]. Interestingly, in a murine model, it has also been shown that exposure of cigarette smoke upregulates IL-33 but simultaneously changes the immune response of IL-33 from Th2 to Th1 response [
59]. Hypothetically, this could explain why smoking may be protective against ulcerative colitis, and potentially also against pSS.
As the patients included in the MSSR are consecutive patients at the only department of rheumatology in the area, we consider the patients in the present study to be representative of the pSS population. Strengths of the present study include the study design, with exposure measured in a standardized manner before pSS diagnosis. The availability of two population-based surveys from a well-defined catchment area and the well-characterized patients with pSS in the MSSR are other important assets of the study.
Limitations of the study are mainly related to the relatively small number of cases. As the number of patients is small there is a risk that the patients are not representative of the whole pSS cohort. Unfortunately, quantitative information on smoking history (i.e. pack-years) was not available. Furthermore, smoking status was only assessed at one time point. All patients came from the same catchment area, which can influence the external validity of the study. With a disease like pSS, there is also always uncertainty about when the disease actually starts. However, in sub-analyses including only cases with symptom onset after the collection of survey data, we calculated similar point estimates on the association between smoking history and pSS, suggesting that reversed causality does not explain our findings.
Acknowledgements
We acknowledge Anders Dahlin for assisting in the gathering of data from the MPMP and MDCS and Jan-Åke Nilsson for valuable input in the statistical analysis.