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Association between cigarette smoking and impaired clinical symptoms in systemic sclerosis: A review
Accepted Manuscript Review article Association between cigarette smoking and impaired clinical symptoms in systemic sclerosis: A review Yan-Jie Zhang, Li Zhang, Xiao-Lei Huang, Yu Duan, Li-Juan Yang, Jing Wang PII: DOI: Reference:
S0008-8749(17)30049-7 http://dx.doi.org/10.1016/j.cellimm.2017.04.002 YCIMM 3643
To appear in:
Cellular Immunology
Received Date: Revised Date: Accepted Date:
10 January 2017 4 March 2017 10 April 2017
Please cite this article as: Y-J. Zhang, L. Zhang, X-L. Huang, Y. Duan, L-J. Yang, J. Wang, Association between cigarette smoking and impaired clinical symptoms in systemic sclerosis: A review, Cellular Immunology (2017), doi: http://dx.doi.org/10.1016/j.cellimm.2017.04.002
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Title page Association between cigarette smoking and impaired clinical symptoms in systemic sclerosis: a review Yan-Jie Zhang1,a, Li Zhang2,a, Xiao-Lei Huang1, Yu Duan1, Li-Juan Yang1, Jing Wang1* 1
Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University,
Hefei, China; 2
Medical Genetics Center, Anhui Medical College, Hefei, China
a
These authors contributed equally to this work and should be considered co-first authors
*
Correspondence author:
Jing Wang, M.D., Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Meishan Road 81, Hefei, Anhui, 230032, PR China, E-mail: [email protected]; Tel.: +86 551 65161175; Fax: +86 551 65161033.
Abstract It has been established that smoking has a profound impact on susceptibility and severity in some rheumatic diseases (e.g., rheumatoid arthritis), a mild impact in others (e.g., systemic lupus erythematosus) through epidemiological studies. And smoking is known to affect many inflammatory and autoimmune diseases through various mechanisms, including immunomodulation and chemical exposure. Although similar studies investigating the role of cigarette exposure in susceptibility to SSc have been rarely reported and specific mechanisms have never been established, the relationship between smoking and some SSc-related symptoms have been demonstrated during the last decade. However, due to the diversity of study designs, control populations, patient populations and the methodology used to determine smoking history, these results are contradictory in some respects. This paper will review current evidence on the association between smoking and SSc and summarize potential mechanisms. Keywords Systemic sclerosis; Cigarette Smoking; Skin; Vascular; Pulmonary 1. Introduction Systemic sclerosis (SSc) is a multisystem disorder that is characterized by microvascular disease, a disturbance in fibroblast function, and activation of the immune system, culminating in fibrosis of the skin and internal organs [1]. Like many other autoimmune and rheumatic diseases, the etiology of SSc is also considered to be multifactorial, with important contributions from multiple genetic and environmental factors, but the pathogenesis of SSc is not yet fully understood. Smoking is one of the most investigated risk factors in epidemiologic studies. It contains innumerable toxic chemicals that could cause genetic mutations and influence both cell-mediated and humoral immune responses harmfully [2]. These changes could eventually, in the course of years or
decades, lead to the development of an autoimmune disease. Recently, smoking has been found to be an environmental risk factor for the development to autoimmune diseases, e.g., rheumatoid arthritis [3] and SLE [4]. Unfortunately, no studies has associated smoking with increased prevalence of SSc, but several associations with disease manifestations have been noted during the last decade. For example, a study published in 2002 found that smokers were 3-4 times more prone to require treatment for digital ischemia [5]. However, conflicting results have been observed in these studies (See Table 1); these might be explained by small sample sizes or the heterogeneity of the study design, the definition of smoking, and the methods used to collect information about tobacco exposure as well as some inherent biases.
If failure to account for these factors may lead to under- or overestimates of the association
between smoking and disease outcomes. Therefore, this paper will review current evidence on the association between smoking and SSc to determine whether cigarette smoking worsens the progression and outcome of SSc from different aspects. 2. The definition of smoking When identifying risks and benefits of smoking in epidemiological studies, one of the key factors is whether the definition of smoking is clear and unambiguous or not, which will directly affects the reliability of these results. Smoking history is a multi-dimensional phenomenon. Smoking status, duration of past smoking, smoking intensity, time since smoking cessation, and age at which smoking started, have all been reported to affect risks of many diseases [8]. Moreover, it will be influenced by the variability of smoking behavior and the reporting bias, the former might be because most patients altered their patterns of smoking after diagnosis or disability increases, and the latter may be because the subjects often answer question according to his perception of social identity when investigating the sensitivity of the issue.
Leffondré et al [9] screened 40 articles published in 2000 in epidemiologic and clinical journals that assessed the impact of smoking on various outcomes and found considerable variation in both the nature of the data collected on smoking history and the way the data were used in the analyses. Thus, there is a need that how to use proper modeling of smoking to avoid potentially biased conclusions. However, there is little consensus regarding how to represent this multidimensional phenomenon in studies on the effect of smoking in SSc patients. Some authors have opted for a rather simplified analysis that focuses on a single aspect of smoking history, thus ignoring the multidimensional aspect of smoking history. For example in one Denmark study [10], smoking was classified as never, current and ex-smoker according to their smoking status. However, due to using simple exposure variables (self-described ever, never or pack-year smoking) that may have resulted in so-called‘healthy smoker bias’in which an individual who smokes may a priori have lungs that are more resistant to the effects of smoking.
Fortunately, other investigators [11] appear to have addressed this controversy by using
the comprehensive smoking index (CSI) which integrates parameters related smoking intensity, duration and time since cessation into a single covariate of smoking effect. One expected benefit of the complexity of the CSI is that it is expected to capture more fully and accurately the effect of smoking, as compared with simpler smoking covariates. For this reason, regression analyses with the CSI are expected to be more sensitive to the detection of smoking effects. Moreover, the CSI has further favorable properties for regression modeling, including improved parsimony and interpretability, and reduced multicollinearity and residual confounding [12]. 3. Smoking on the susceptibility to SSc Investigations into the potential impact of tobacco exposure on the development and outcome of certain autoimmune diseases, in particular rheumatoid arthritis (RA) and systemic lupus erythematosus
(SLE), have been carried out extensively during the last decade [3, 4, 13]. There are various studies demonstrated that cigarette smoking is associated with worse disease manifestations of SSc, but the role of cigarette smoking as a risk factor for disease susceptibility in SSc has been rarely reported. In order to investigate the association of smoking with susceptibility to SSc, a case-control study by Prateek Chaudhary et al [14] were performed in a large, well-defined patient population, and they concluded that smoking does not confer a risk for development of SSc, even though it may impact disease severity. The use of simplified analyses that focused on a single aspect of smoking (ever versus never smoked) is the major limitation in this study. Moreover, this result could potentially have been influenced by the effect of SSc on smoking habits, namely, that the diagnosis of SSc is a strong incentive for smoking cessation that does not exist for control subjects, which likely cause the percentage of patients is no higher than control subjects who are current smokers. In addition, this study did not match or adjust for other potentially important variables such as socioeconomic status or alcohol consumption. As we all know, lower socioeconomic status and drinking alcohol are associated with cigarette smoking, and in some studies [13, 15] alcohol consumption was shown to be inversely associated with the risk of autoimmune disease. Thus, further high-quality studies are needed to confirm this result. Overall, the results of the current study do not indicate that smoking influences the susceptibility to SSc. So larger studies are needed to evaluate whether cigarette smoking as well as the duration or quantity of cigarettes smoked (i.e., smoking intensity) has an impact on the susceptibility to SSc. Moreover, there has been growing concern that non-smokers may also be at risk for some of the cigarette smoke-associated diseases as a result of involuntary exposure to environmental tobacco smoke [16]. And the chemical composition of environmental tobacco smoke is very similar to
mainstream tobacco smoke and may predispose people to SSc. So in vitro and animal studies may further help to shed light on the biologic mechanisms and pathways by which cigarette smoke may play a role in the etiology of SSc. 4. Association of smoking with clinical symptoms of SSc Although there are no studies indicate that smoking influences the susceptibility to SSc, the relationship between smoking and some SSc-related symptoms have been demonstrated (See Table 1). For example, it has been suggested that cigarette smoking was associated with the vascular, gastrointestinal, and respiratory outcomes of SSc, but a common theme is lacking. To make an understanding of the effect of cigarette smoking on SSc, the following will examine the effect of smoking on some specific manifestations of SSc, including skin destruction, vascular complications and other organ involvement. 4.1 Skin destruction SSc is very heterogeneous, but skin involvement is nearly universal and two common clinical subsets based on the extent of skin involvement are typically recognized, namely limited SSc with skin involvement below the elbows and knees and diffuse SSc with skin involvement of the proximal limbs and/or trunk [17]. But nothing is known about the effect of smoking on skin disease in SSc. To study the effect of cigarette smoking on the extent of skin disease in SSc, a recent 20-month follow-up study in Italian was performed [18], the researchers observed that there was no statistically significant difference in smoking habits between the two groups of patients with or without skin ulcers (P = 0.274). Furthermore, when analyzing patients with fingertip or other ulcers, they also found no significant difference in smoking between the two subgroups of patients (P = 0.30). Moreover, Khimdas et al [19] also found that digital ulcers were not associated with smoking (P = 0.9). However, McCullagh and
colleagues [20] used negative binomial regression to determine the association between the extent of skin involvement (the extent of skin involvement was assessed using the modified Rodnan skin score [21]) and smoking, and concluded that smoking was significantly associated with less extensive skin disease in SSc and the effect of smoking on skin disease appeared cumulative and irreversible. But the “protective” effect of cigarette smoking on SSc skin found in this study may be influenced by the angiogenic properties of nicotine even though some microvascular surgeons have also used animal models to show that smoking delays wound healing and increases the risk of skin flap necrosis [22]. Because the angiogenic property of nicotine has been hypothesized to have a positive effect on wound healing [23] and also ameliorate disorders characterized by inadequate angiogenesis. Since defects in angiogenesis are implicated in the pathophysiology of SSc [24], it is possible that the effect of smoking found in this study could be mediated by the angiogenic effects of nicotine. Finally, we believe that these studies provide new avenue of research, especially further research in SSc pathogenesis should take into account the role of nicotine in SSc and this would be an interesting area for future study. 4.2 Vascular complications In recent studies, several factors have been implicated in the pathogenesis of vascular disease in SSc, including damage to the vascular endothelium, hypercoagulability, and reduced fibrinolysis [25, 26]. Smoking has been shown to increase the risk of vascular complications in other autoimmune diseases, such as systemic vasculitis in patients with rheumatoid arthritis [27], and progression to end-stage renal disease in those with lupus nephritis. However, previous studies on the effect of cigarette smoking on vascular disease in SSc have had contradictory results. For example, in a study conducted at Johns Hopkins Medical Center in Baltimore (involving 98 patients 13% of whom were
smokers, with smoking assessed as never, former, or current), smoking was not a risk factor for digital ulceration or amputation [28]. In contrast, in a subsequent study conducted at Hope Hospital in Manchester, UK (involving 101 patients, 21% of whom were smokers, with smoking assessed as never, past, or current and as pack-years), current smokers were 3-4 times more likely than never smokers to incur digital vascular complications [18]. However, past smokers were not at increased risk compared with never smokers. Moreover, only those subjects in the highest tertile of smoking intensity (23–51 pack-years) showed a trend toward having more vascular disease. There is no doubt that these differences are mainly due to the heterogeneity within current and past smokers and the biases inherent in modeling smoking exposure. A recent study appears to have addressed this controversy by using the comprehensive smoking index (CSI) [12], they selected 3 clinical outcomes, namely, severity of Raynaud’s phenomenon, presence of acid reflux, and changes in the DLCO to illustrate how the CSI is a measure that can flexibly model different functional forms of smoking in relation to outcomes of interest, and they concluded that the deleterious effects of smoking on the severity of Raynaud’s phenomenon and the presence of finger ulcers were clearly demonstrated when using the CSI. Moreover, they also find that the severity of Raynaud’s phenomenon is an example of an outcome with a short half-life (s =1 year) and short lag-time (d= 0.2 years). This suggests that the severity of Raynaud’s phenomenon is affected by smoking mainly in current smokers, and that once the patient stops smoking, the effect disappears. In conclusion, studies have shown that cigarette smokers with SSc are significantly more likely than nonsmokers to require treatment for digital vascular disease and current smokers had more severe vascular disease than did ex-smokers. On the other hand, we propose that further research in SSc pathogenesis should take into account the similarities with smoking-related vascular disease and this
might better explain the role of smoking on vascular disease in SSc. 4.3 Pulmonary involvement Pulmonary involvement is a prominent feature in systemic sclerosis and a significant cause of morbidity and mortality [29]. The types of impairment include reduced diffusing capacity of carbon monoxide (DLco) as an isolated abnormality and reduced diffusing capacity in patients with restrictive lung disease. According to some studies smoking may also reduce the lung function of patients with SSc. For example, Steen et al [30] have shown that SSc patients who smoked revealed more frequent and severe obstructive changes. Smoking patients with restrictive lung disease had more severe disease than nonsmoking patients, and their single-breath diffusing capacity for carbon monoxide was significantly decreased compared with the nonsmokers. Furthermore, some authors also demonstrated that the maximal mid-expiratory flow rate, closing volume and closing capacity were nearly always normal in nonsmokers, but frequently abnormal in smokers with SSc and interpreted that small airway involvement was related to the smoking habit. However, others have failed to confirm this result. Greenwald et al. [31] demonstrated that nonsmokers had greater rates of decline in total lung capacity and static lung compliance than did current and former smokers. Some other authors have also reported that pulmonary function in nonsmokers was not different and that it did not change at rates different from those in a nonsmoking reference population [32]. This means that individual variability in the course of pulmonary function is large and not completely explained by smoking status. Some other authors have also reported that pulmonary function in nonsmokers was not different and that it did not change at rates different from those in a nonsmoking reference population. In addition, a Cross-sectional study by McNearney et al [33] showed that there was a significantly higher percentage of patients with SSc with an obstructive lung pattern in the current smoking group
compared with the current non-smoking group (P= 0.008). Further delineating the nonsmoking patient group into previous smokers and never smokers demonstrated a significant difference between the percentage of patients with an obstructive pattern (P=0.03). Furthermore, the effect of smoking on lung cancer of SSc has also been investigated. A nested case–control study by Freemer et al [34] demonstrated that patients with SSc who smoke are seven times more likely to develop lung cancer than non-smokers ( P= 0.008), which is similar to that seen in the UK general population [35]. The effect of smoking on pulmonary involvement is intriguing. Although an association between smoking and declining pulmonary function in SSc patients has been shown, it would be better to identify any subgroups of SSc patients that are particularly susceptible to smoking. Because it has been shown that different patterns of pulmonary involvement are seen in different subtypes of SSc [36]. On the other hand, due to the effect of “a healthy smoker”, there is a need to clarify the mechanisms of smoking-induced lung disease in SSc. 4.4 Other organ impairment Smoking has been reported to worsen acid reflux in gastrointestinal disease [37]. According to the report, the GI tract is also involved in around 90% of all patients with SSc. But it is unclear whether the gastrointestinal involvement are also influenced by smoking in SSc. Hudson et al [12] recently explored the association between smoking and various clinical problems in SSc. They found that smoking significantly increased the risk of GI symptoms and poor appetite. Moreover, in addition to above problems, the relationship between smoking and other organ problems have also been explored in recent years. For example, one study [38] from Canadian was attempted to determine whether cigarette smoking worsens the sleep disruption in patients with SSc, results showed that smoking were associated with sleep scores in bivariate analyses. Beyond that, Thombs and colleagues [39] used a
hierarchical multiple linear regression to assess multivariable associations between demographic (step 1), socioeconomic (step 2), global disease (step 3), specific disease and life-style factors (step 4), and depression and pain (step 5) with fatigue (SF-36 vitality subscale scores) in SSc, and found that higher fatigue was significantly associated with current smoking (standardized β=0.08, P =0.018). On the other hand, another study [40] have demonstrated that survival was decreased in past or present smokers
compared with those who had never smoked. Cox proportional hazards regression
revealed that the significant hazard ratio (HR) of 1.53 (95% CI 1.02–2.30, P =0.038) persisted after stratification by sex and adjustment for age at disease onset. This risk was higher in current smokers (HR 1.93 [95% CI 1.09–3.44]) as compared to those who had stopped smoking (HR 1.28 [95% CI 0.81–2.03]). Further, survival in smokers decreased with increasing pack-years in those with a history of ≥40 pack-years, demonstrating an HR of 2.21 (95% CI 1.33–3.66, P = 0.002), after adjustment for sex and age at disease onset. The effect of smoking on the clinical symptoms in SSc patients is very complicated, because such patients are likely to have more severe disease, this is likely to influence the relationship between cigarette smoking and these clinical symptoms. It is also important to consider whether patients with more severe disease started smoking after they had an organ involvement. Thus, further investigation on the true pathogenesis and nature of smoking in systemic sclerosis should be performed. 5. Potential mechanisms of smoking and SSc Although the biologic pathway through which cigarette smoking acts to increase the risk of SSc is not completely understood, previous studies have had some review articles [41, 42] to explain in detail the biologic effect of smoking on the development of autoimmune rheumatic diseases. Here, we make a detailed introduction to these mechanisms. (Fig.1)
First, cigarette smoke contains thousands of chemicals that have cytotoxic, mutagenic, carcinogenic, or antigenic properties [2]. The products of combustion can be divided into gaseous and particulate components, both of which contain extremely high concentrations of free radicals and cigarette smoke activates endogenous sources of free radicals as well. Reactive oxidative species (ROS) produced from the metabolism of constituents of tobacco smoke and free radicals can interact with DNA, and could cause genetic mutations [18]. Indeed, a significantly higher risk of anti-dsDNA seropositivity in current smokers with SLE than in never smokers has been demonstrated. For example, smoke, by provoking oxidative stress, may contribute to lupus disease by dysregulating DNA demethylation, upregulating immune genes thereby leading to autoreactivity [43]. This, therefore, might have a role in the development of autoimmune disease. Second, combustion is an important step that produces reactive oxidative substances (ROS), which activate epithelial cell intracellular signaling cascades that lead to inflammatory gene activation [e.g., IL-8 and tumor necrosis factor-alpha (TNFα)] [44] , therefore, initiate inflammatory processes. Third, there is increasing evidence that nicotine, a major component in cigarette smoke, may have an immunosuppressive effect [42]. It induces abnormalities in T cells, reduces the activity of natural killer cells and decreases serum levels of IgM and IgG. These modulations in both cellular and humoral immunity might contribute to the induction of autoimmune processes. Fourth, cigarette smoking has anti-estrogenic effects through the formation of inactive 2-hydroxy catechol estrogens [18]. Estrogens can affect the Thl/Th2 immune balance and estrogens have either pro- or anti-inflammatory actions depending on the estrogen/androgen balance [45]. Through the modulation of hormonal balance, smoking might, therefore, enhance inflammatory processes.
In summary, the mechanisms by which smoking affects autoimmune diseases are multiple and complex. Continued exploration of how cigarette smoking acts as a trigger of autoimmunity is necessary. Animal models and basic research into the biologic effects of the constituents of cigarette smoke, as well as ongoing large cohort studies will advance our understanding of disease mechanisms. And the search for gene-environment interactions involving smoking and other environmental exposures should proceed in parallel.
6. Discussion This is a comprehensive study investigating the effect of smoking on multiple outcomes in patients with SSc. Although previous results do not convincingly support that patients with SSc are at a significantly increased risk for developing smoking, various studies have show convincingly that smoking was associated with a significant negative impact on skin, vascular, gastrointestinal, and respiratory outcomes in SSc [5, 11, 12, 33, 34, 38, 46, 47], and that these effects might be long-lasting (e.g., respiratory outcomes). Moreover, there are epidemiology and basic studies shown that smoking can affect these symptoms by different mechanisms (See Figure 1). Therefore, we believe that smoking cessation could have a protective effect against the development of SSc and these patients should be recommended to abstain from smoking. Unfortunately, epidemiological data often are obtained from retrospective studies and underpowered case-control studies, which often suffer from some shortcomings in methodology. As we all know, SSc is a rare disease, with a prevalence in the North America between 3 and 24 per 100,000 population [48]. It is therefore difficult to recruit large numbers of patients for investigation, so some studies used a convenience sample of SSc patients enrolled in the Registration System, but patients in the Registry may overrepresent relatively healthy SSc patients, as opposed to patients with severe SSc
who may have been too sick to participate or died early in their disease course. In addition, because of the diversity of study designs, control populations, patient populations, and the methodology used to determine smoking history, the results will be contradictory between different researches. For example, it may be that persons with one established chronic illness are more likely to be aware of (or to report) comorbidity due to the fact that they have more contact with the medical system than persons in the general population, which might create a ‘detection’ bias. So it is clear that failure to account for these biases may lead to under- or overestimates of the association between smoking and disease outcomes. Therefore, there are so many precautions need to be considered in future studies. First, it is better to use unified measuring scale (for example, the CSI) to determine smoking history in epidemiological studies. And future studies in SSc should also aim to gather a larger number of moderate to heavy smokers. Second, it is very important that selecting reasonably the patients and control groups and match out those suspected confounding factors (e.g. drinking or along with other diseases) in future studies of the relationship between smoking and SSc. Third, how genetics and environmental factors interact in SSc pathogenesis and development? The interaction of smoking (as an environmental factor) with genetic susceptibility might further complicate the understanding of these mechanisms. So it is worthwhile to study smoking interactions with genetic susceptibility and other exposures such as virus infection which could lead to dangerous negative interactions in the onset and progression of the disease. And last, the mechanism of smoking on SSc risk may be quite complicated. Therefore, larger prospective longitudinal clinical and epidemiological studies are necessary, preferably complemented
by specific animal model studies as well as parallel laboratory testing to better understand the role of smoking in SSc.
7. Conclusion In conclusion, this review suggested that smoking increased the risk of skin, vascular, gastrointestinal, and respiratory outcomes in SSc. There is a need, therefore, those SSc patients should prioritize smoking cessation as part of the management of the disease. In addition, the mechanisms by which smoking affects autoimmune rheumatic diseases are multiple and complex. Further epidemiological data and animal studies are needed to done in order to fully appreciate the role of smoking in these diseases. Acknowledgements This work was partly supported by grants from the Anhui Provincial Laboratory of Population Health & Major Disease Screening and Diagnosis, the Key Project of the Education Department of Anhui Province Natural Science Research. Conflict of interest The authors declare no conflicts of interest. Reference 1.
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38. Milette K, Razykov I, Pope J, Hudson M, Motivala SJ, Baron M, et al. Clinical correlates of sleep problems in systemic sclerosis: the prominent role of pain. Rheumatology. 2011;50(5):921-5. 39. Thombs B D, Hudson M, Bassel M, et al. Sociodemographic, disease, and symptom correlates of fatigue in systemic sclerosis: Evidence from a sample of 659 Canadian Scleroderma Research Group Registry patients[J]. Arthritis & Rheumatology, 2009, 61(7):966–973. 40. Foocharoen C, Nanagara R, Kiatchoosakun S, Suwannaroj S, Mahakkanukrauh A. Prognostic factors of mortality and 2-year survival analysis of systemic sclerosis with pulmonary arterial hypertension in Thailand. International Journal of Rheumatic Diseases. 2011;14(3):282–9. 41. Harel-Meir M, Sherer Y, Shoenfeld Y. Tobacco smoking and autoimmune rheumatic diseases. Nature Clinical Practice Rheumatology. 2007;3(3):707-15. 42. Costenbader KH, Karlson EW. Cigarette smoking and autoimmune disease: what can we learn from epidemiology? Lupus. 2006;15(11):737-45. 43. Strickland FM, Li YP, Johnson K, Sun Z, Richardson BC. CD4 + T cells epigenetically modified by oxidative stress cause lupus-like autoimmunity in mice. Journal of Autoimmunity. 2015;62:75-80. 44. Chung KF. Inflammatory mediators in chronic obstructive pulmonary disease. Current Drug Targets - Inflammation & Allergy. 2005;4(6):619-25. 45. Cutolo M. Sex and rheumatoid arthritis: Mouse model versus human disease. Arthritis & Rheumatism. 2007;56(1):1-3. 46. Gyger G, Hudson M, Lo E, et al. Does cigarette smoking mitigate the severity of skin disease in systemic sclerosis?[J]. Rheumatology International, 2013, 33(4):943-8.
47. Quadrelli S A, Molinari L, Ciallella L M, et al. Patterns of pulmonary function in smoking and nonsmoking patients with progressive systemic sclerosis[J]. Rheumatology International, 2009, 29(9):995-9. 48. Carmi G, Amital H. The geoepidemiology of autoimmunity: capsules from the 7th International Congress on Autoimmunity, Ljubljana, Slovenia, May 2010. Israel Medical Association Journal Imaj. 2011;13(2):121-7.
Highlights
1. This is a comprehensive study investigating the effect of smoking on multiple outcomes in patients with SSc. 2. Smoking was associated with a significant negative impact on digital ulcers, pulmonary function, and lung cancer in SSc.3. Cigarette smoking can interact with DNA and could cause genetic mutations. It can also cause inflammatory gene activation. In addition, cigarette smoking has also many other adverse effects on the onset of SSc, such as causing inflammation and impairing immune functiont; Finally, smoking has anti-estrogenic effects through the formation of inactive 2-hydroxy catechol estrogens.
Cigarette Smoking
T /B cells NK cell、 、 Macrophages activity
Gene-smoking interaction
Inactive 2-hydroxy catechol estrogens
Inflammatory gene activation
Alteraction of cytokines
(IL-1、 、 IL-8、 、 TNFα)
IgG anti-dsDNA
Anti-estrogenic
antibodies
effects
IL-6、 、 CRP
Inflammatory
Immune dysregulation
SSc
Fig 1 Cigarette smoking affects the SSc in diverse ways. Cigarette smoking can interact with DNA and could cause genetic mutations. It can also cause inflammatory gene activation (eg. IL-1 and IL-8). In addition, cigarette smoking has also many other adverse effects on the onset of SSc, such as causing inflammation and impairing immune functiont; Finally, smoking has anti-estrogenic effects through the formation of inactive 2-hydroxy catechol estrogens. Abbreviations: CRP, C-reactive protein; TNFα , tumor necrosis factor.
Table 1
The association between cigarette smoking and various clinical symptoms of SSc patients. Smoke First Type of study and methods Patients (past/present) Outcomes author,year (%) OR for SSc in smokers vs never sm Chaudhary Cross-sectional study; 1379 43/42.5 2011 621 cases and 1228 controls 0.839- 1.240). OR for SSc in smokers vs never sm Atteritano Case-Control study; 54 31.5/29.6 2013 54 cases and 54 controls 0.481- 2.475). OR for SSc in smokers vs never sm Pischon Case-Control study; 58 53.4/40.4 2016 58 cases and 52 controls 0.823- 3.766). Cross-sectional study; Smoking was significantly associated Caramaschi 29 digital ulcers and 56 85 34.5/8.9 SSc. 2009 without digital ulcers P=0.003, OR: 2.46 (1.45- 4.15) Cross-sectional study; Smoking was not a risk factor for skin Alivernini 34 skin ulcers and 96 130 8.8/14.6 P=0.274, OR: 0.64(0.22- 1.88 ) 2009 without digital ulcers Khimdas Smoking was not a risk factor for digi Cross-sectional study; 938 71.6 2011 P=0.909, OR:0.984 Current smokers are 3-4 times never-smokers to incur digital vascula Harrison Cross-sectional study; 101 57.4 OR: 3.8(1.1-12.9) for Admission for I 2002 OR: 4.5 (1.1-18.3) for Digital Debride OR: 3.4 (0.8-15.1) for Digital Amputa Smoking was significantly associa Genevie`ve Cross-sectional study; 606 57.9 skin disease in SSc. Gyger,2012 P=0.0029, OR:0.84(0.75-0.95) Cross-sectional study; Smoking was not associated with pulm Broholm 30 pulmonary fibrosis and 155 43.3/55.2 P=0.246, OR:0.68(0.36-1.30) 2008 125 non pulmonary fibrosis Smoking was significantly associate Nested case-control study; Freemer SSc patients. 20 lung cancer and 41 61 90.0/56.1 2007 P=0.016, OR=7.04 ( 1.44-34.39 ) gender-matched controls The smokers had a significantly highe Silvia Cross-sectional study; 46 26.1 2008 percentage of predicted (P = 0.036, P= Smoking appears to have an additiv Cross-sectional study; Steen pulmonary function in SSc patients.(P 137 smoking SSc and 165 302 45.4 1985 OR for Restrictive 1.908 (95% CI: 1.0 nonsmoking patients OR for Obstructive 4.387 (95% CI: 2. Higher obstructive and restrictive lun TERRY Cross-sectional study; 203 23.6 smokers compared with the 2007 P=0.062, respectively) Kang Cross-sectional study; Smoking was not associated with canc 112 11.1/3.7 2009 9 SSc with cancer and 103 P= 0.326,OR: 0.304(0.028-3.273)
Thombs 2009 Hudson 2011 BRETT D.2009 Milette 2011 Vemulapalli 2016 Santosa 2016 Hissaria 2011
without cancer Cross-sectional study; 81abnormal Pap test and 239 without abnormal Pap test
320
25.9/13.4
Cross-sectional study;
606
57.9
Cross-sectional study;
659
15.9
Cross-sectional study;
70
15.7
300
47.4/32.9
349
12.3
786
47.7
Cross-sectional study; 133 SSc with diastolic dysfunction and 167 controls Cohort study; systemic sclerosis cohort Singapore (SCORE) Cohort study; South Australian Scleroderma Register (SASR)
Smoking was significantly associated cancer screening (Pap test) in SSc pati P=0.008, OR:2.43(1.23, 4.78)
The number of GI symptoms, poor a showed statistical significant smoking.(P=0.03, P=0.03, P=0.01, res Higher fatigue was significantly a smoking ( P =0.018). Sleep disruption was associated with bivariate analyses. Smoking was significantly assoc dysfunction in SSc patients. P=0.011 , OR:1.833 ( 1.147-2.930)
Multivariate analysis showed that sm was independ CI: 1.5-10.6] mortality.(P=0.016) Cox proportional hazards regressi significant HR of 1.53 (95% CI 1.02–2.30, P= 0.0
S0008-8749(17)30049-7 http://dx.doi.org/10.1016/j.cellimm.2017.04.002 YCIMM 3643
To appear in:
Cellular Immunology
Received Date: Revised Date: Accepted Date:
10 January 2017 4 March 2017 10 April 2017
Please cite this article as: Y-J. Zhang, L. Zhang, X-L. Huang, Y. Duan, L-J. Yang, J. Wang, Association between cigarette smoking and impaired clinical symptoms in systemic sclerosis: A review, Cellular Immunology (2017), doi: http://dx.doi.org/10.1016/j.cellimm.2017.04.002
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Title page Association between cigarette smoking and impaired clinical symptoms in systemic sclerosis: a review Yan-Jie Zhang1,a, Li Zhang2,a, Xiao-Lei Huang1, Yu Duan1, Li-Juan Yang1, Jing Wang1* 1
Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University,
Hefei, China; 2
Medical Genetics Center, Anhui Medical College, Hefei, China
a
These authors contributed equally to this work and should be considered co-first authors
*
Correspondence author:
Jing Wang, M.D., Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Meishan Road 81, Hefei, Anhui, 230032, PR China, E-mail: [email protected]; Tel.: +86 551 65161175; Fax: +86 551 65161033.
Abstract It has been established that smoking has a profound impact on susceptibility and severity in some rheumatic diseases (e.g., rheumatoid arthritis), a mild impact in others (e.g., systemic lupus erythematosus) through epidemiological studies. And smoking is known to affect many inflammatory and autoimmune diseases through various mechanisms, including immunomodulation and chemical exposure. Although similar studies investigating the role of cigarette exposure in susceptibility to SSc have been rarely reported and specific mechanisms have never been established, the relationship between smoking and some SSc-related symptoms have been demonstrated during the last decade. However, due to the diversity of study designs, control populations, patient populations and the methodology used to determine smoking history, these results are contradictory in some respects. This paper will review current evidence on the association between smoking and SSc and summarize potential mechanisms. Keywords Systemic sclerosis; Cigarette Smoking; Skin; Vascular; Pulmonary 1. Introduction Systemic sclerosis (SSc) is a multisystem disorder that is characterized by microvascular disease, a disturbance in fibroblast function, and activation of the immune system, culminating in fibrosis of the skin and internal organs [1]. Like many other autoimmune and rheumatic diseases, the etiology of SSc is also considered to be multifactorial, with important contributions from multiple genetic and environmental factors, but the pathogenesis of SSc is not yet fully understood. Smoking is one of the most investigated risk factors in epidemiologic studies. It contains innumerable toxic chemicals that could cause genetic mutations and influence both cell-mediated and humoral immune responses harmfully [2]. These changes could eventually, in the course of years or
decades, lead to the development of an autoimmune disease. Recently, smoking has been found to be an environmental risk factor for the development to autoimmune diseases, e.g., rheumatoid arthritis [3] and SLE [4]. Unfortunately, no studies has associated smoking with increased prevalence of SSc, but several associations with disease manifestations have been noted during the last decade. For example, a study published in 2002 found that smokers were 3-4 times more prone to require treatment for digital ischemia [5]. However, conflicting results have been observed in these studies (See Table 1); these might be explained by small sample sizes or the heterogeneity of the study design, the definition of smoking, and the methods used to collect information about tobacco exposure as well as some inherent biases.
If failure to account for these factors may lead to under- or overestimates of the association
between smoking and disease outcomes. Therefore, this paper will review current evidence on the association between smoking and SSc to determine whether cigarette smoking worsens the progression and outcome of SSc from different aspects. 2. The definition of smoking When identifying risks and benefits of smoking in epidemiological studies, one of the key factors is whether the definition of smoking is clear and unambiguous or not, which will directly affects the reliability of these results. Smoking history is a multi-dimensional phenomenon. Smoking status, duration of past smoking, smoking intensity, time since smoking cessation, and age at which smoking started, have all been reported to affect risks of many diseases [8]. Moreover, it will be influenced by the variability of smoking behavior and the reporting bias, the former might be because most patients altered their patterns of smoking after diagnosis or disability increases, and the latter may be because the subjects often answer question according to his perception of social identity when investigating the sensitivity of the issue.
Leffondré et al [9] screened 40 articles published in 2000 in epidemiologic and clinical journals that assessed the impact of smoking on various outcomes and found considerable variation in both the nature of the data collected on smoking history and the way the data were used in the analyses. Thus, there is a need that how to use proper modeling of smoking to avoid potentially biased conclusions. However, there is little consensus regarding how to represent this multidimensional phenomenon in studies on the effect of smoking in SSc patients. Some authors have opted for a rather simplified analysis that focuses on a single aspect of smoking history, thus ignoring the multidimensional aspect of smoking history. For example in one Denmark study [10], smoking was classified as never, current and ex-smoker according to their smoking status. However, due to using simple exposure variables (self-described ever, never or pack-year smoking) that may have resulted in so-called‘healthy smoker bias’in which an individual who smokes may a priori have lungs that are more resistant to the effects of smoking.
Fortunately, other investigators [11] appear to have addressed this controversy by using
the comprehensive smoking index (CSI) which integrates parameters related smoking intensity, duration and time since cessation into a single covariate of smoking effect. One expected benefit of the complexity of the CSI is that it is expected to capture more fully and accurately the effect of smoking, as compared with simpler smoking covariates. For this reason, regression analyses with the CSI are expected to be more sensitive to the detection of smoking effects. Moreover, the CSI has further favorable properties for regression modeling, including improved parsimony and interpretability, and reduced multicollinearity and residual confounding [12]. 3. Smoking on the susceptibility to SSc Investigations into the potential impact of tobacco exposure on the development and outcome of certain autoimmune diseases, in particular rheumatoid arthritis (RA) and systemic lupus erythematosus
(SLE), have been carried out extensively during the last decade [3, 4, 13]. There are various studies demonstrated that cigarette smoking is associated with worse disease manifestations of SSc, but the role of cigarette smoking as a risk factor for disease susceptibility in SSc has been rarely reported. In order to investigate the association of smoking with susceptibility to SSc, a case-control study by Prateek Chaudhary et al [14] were performed in a large, well-defined patient population, and they concluded that smoking does not confer a risk for development of SSc, even though it may impact disease severity. The use of simplified analyses that focused on a single aspect of smoking (ever versus never smoked) is the major limitation in this study. Moreover, this result could potentially have been influenced by the effect of SSc on smoking habits, namely, that the diagnosis of SSc is a strong incentive for smoking cessation that does not exist for control subjects, which likely cause the percentage of patients is no higher than control subjects who are current smokers. In addition, this study did not match or adjust for other potentially important variables such as socioeconomic status or alcohol consumption. As we all know, lower socioeconomic status and drinking alcohol are associated with cigarette smoking, and in some studies [13, 15] alcohol consumption was shown to be inversely associated with the risk of autoimmune disease. Thus, further high-quality studies are needed to confirm this result. Overall, the results of the current study do not indicate that smoking influences the susceptibility to SSc. So larger studies are needed to evaluate whether cigarette smoking as well as the duration or quantity of cigarettes smoked (i.e., smoking intensity) has an impact on the susceptibility to SSc. Moreover, there has been growing concern that non-smokers may also be at risk for some of the cigarette smoke-associated diseases as a result of involuntary exposure to environmental tobacco smoke [16]. And the chemical composition of environmental tobacco smoke is very similar to
mainstream tobacco smoke and may predispose people to SSc. So in vitro and animal studies may further help to shed light on the biologic mechanisms and pathways by which cigarette smoke may play a role in the etiology of SSc. 4. Association of smoking with clinical symptoms of SSc Although there are no studies indicate that smoking influences the susceptibility to SSc, the relationship between smoking and some SSc-related symptoms have been demonstrated (See Table 1). For example, it has been suggested that cigarette smoking was associated with the vascular, gastrointestinal, and respiratory outcomes of SSc, but a common theme is lacking. To make an understanding of the effect of cigarette smoking on SSc, the following will examine the effect of smoking on some specific manifestations of SSc, including skin destruction, vascular complications and other organ involvement. 4.1 Skin destruction SSc is very heterogeneous, but skin involvement is nearly universal and two common clinical subsets based on the extent of skin involvement are typically recognized, namely limited SSc with skin involvement below the elbows and knees and diffuse SSc with skin involvement of the proximal limbs and/or trunk [17]. But nothing is known about the effect of smoking on skin disease in SSc. To study the effect of cigarette smoking on the extent of skin disease in SSc, a recent 20-month follow-up study in Italian was performed [18], the researchers observed that there was no statistically significant difference in smoking habits between the two groups of patients with or without skin ulcers (P = 0.274). Furthermore, when analyzing patients with fingertip or other ulcers, they also found no significant difference in smoking between the two subgroups of patients (P = 0.30). Moreover, Khimdas et al [19] also found that digital ulcers were not associated with smoking (P = 0.9). However, McCullagh and
colleagues [20] used negative binomial regression to determine the association between the extent of skin involvement (the extent of skin involvement was assessed using the modified Rodnan skin score [21]) and smoking, and concluded that smoking was significantly associated with less extensive skin disease in SSc and the effect of smoking on skin disease appeared cumulative and irreversible. But the “protective” effect of cigarette smoking on SSc skin found in this study may be influenced by the angiogenic properties of nicotine even though some microvascular surgeons have also used animal models to show that smoking delays wound healing and increases the risk of skin flap necrosis [22]. Because the angiogenic property of nicotine has been hypothesized to have a positive effect on wound healing [23] and also ameliorate disorders characterized by inadequate angiogenesis. Since defects in angiogenesis are implicated in the pathophysiology of SSc [24], it is possible that the effect of smoking found in this study could be mediated by the angiogenic effects of nicotine. Finally, we believe that these studies provide new avenue of research, especially further research in SSc pathogenesis should take into account the role of nicotine in SSc and this would be an interesting area for future study. 4.2 Vascular complications In recent studies, several factors have been implicated in the pathogenesis of vascular disease in SSc, including damage to the vascular endothelium, hypercoagulability, and reduced fibrinolysis [25, 26]. Smoking has been shown to increase the risk of vascular complications in other autoimmune diseases, such as systemic vasculitis in patients with rheumatoid arthritis [27], and progression to end-stage renal disease in those with lupus nephritis. However, previous studies on the effect of cigarette smoking on vascular disease in SSc have had contradictory results. For example, in a study conducted at Johns Hopkins Medical Center in Baltimore (involving 98 patients 13% of whom were
smokers, with smoking assessed as never, former, or current), smoking was not a risk factor for digital ulceration or amputation [28]. In contrast, in a subsequent study conducted at Hope Hospital in Manchester, UK (involving 101 patients, 21% of whom were smokers, with smoking assessed as never, past, or current and as pack-years), current smokers were 3-4 times more likely than never smokers to incur digital vascular complications [18]. However, past smokers were not at increased risk compared with never smokers. Moreover, only those subjects in the highest tertile of smoking intensity (23–51 pack-years) showed a trend toward having more vascular disease. There is no doubt that these differences are mainly due to the heterogeneity within current and past smokers and the biases inherent in modeling smoking exposure. A recent study appears to have addressed this controversy by using the comprehensive smoking index (CSI) [12], they selected 3 clinical outcomes, namely, severity of Raynaud’s phenomenon, presence of acid reflux, and changes in the DLCO to illustrate how the CSI is a measure that can flexibly model different functional forms of smoking in relation to outcomes of interest, and they concluded that the deleterious effects of smoking on the severity of Raynaud’s phenomenon and the presence of finger ulcers were clearly demonstrated when using the CSI. Moreover, they also find that the severity of Raynaud’s phenomenon is an example of an outcome with a short half-life (s =1 year) and short lag-time (d= 0.2 years). This suggests that the severity of Raynaud’s phenomenon is affected by smoking mainly in current smokers, and that once the patient stops smoking, the effect disappears. In conclusion, studies have shown that cigarette smokers with SSc are significantly more likely than nonsmokers to require treatment for digital vascular disease and current smokers had more severe vascular disease than did ex-smokers. On the other hand, we propose that further research in SSc pathogenesis should take into account the similarities with smoking-related vascular disease and this
might better explain the role of smoking on vascular disease in SSc. 4.3 Pulmonary involvement Pulmonary involvement is a prominent feature in systemic sclerosis and a significant cause of morbidity and mortality [29]. The types of impairment include reduced diffusing capacity of carbon monoxide (DLco) as an isolated abnormality and reduced diffusing capacity in patients with restrictive lung disease. According to some studies smoking may also reduce the lung function of patients with SSc. For example, Steen et al [30] have shown that SSc patients who smoked revealed more frequent and severe obstructive changes. Smoking patients with restrictive lung disease had more severe disease than nonsmoking patients, and their single-breath diffusing capacity for carbon monoxide was significantly decreased compared with the nonsmokers. Furthermore, some authors also demonstrated that the maximal mid-expiratory flow rate, closing volume and closing capacity were nearly always normal in nonsmokers, but frequently abnormal in smokers with SSc and interpreted that small airway involvement was related to the smoking habit. However, others have failed to confirm this result. Greenwald et al. [31] demonstrated that nonsmokers had greater rates of decline in total lung capacity and static lung compliance than did current and former smokers. Some other authors have also reported that pulmonary function in nonsmokers was not different and that it did not change at rates different from those in a nonsmoking reference population [32]. This means that individual variability in the course of pulmonary function is large and not completely explained by smoking status. Some other authors have also reported that pulmonary function in nonsmokers was not different and that it did not change at rates different from those in a nonsmoking reference population. In addition, a Cross-sectional study by McNearney et al [33] showed that there was a significantly higher percentage of patients with SSc with an obstructive lung pattern in the current smoking group
compared with the current non-smoking group (P= 0.008). Further delineating the nonsmoking patient group into previous smokers and never smokers demonstrated a significant difference between the percentage of patients with an obstructive pattern (P=0.03). Furthermore, the effect of smoking on lung cancer of SSc has also been investigated. A nested case–control study by Freemer et al [34] demonstrated that patients with SSc who smoke are seven times more likely to develop lung cancer than non-smokers ( P= 0.008), which is similar to that seen in the UK general population [35]. The effect of smoking on pulmonary involvement is intriguing. Although an association between smoking and declining pulmonary function in SSc patients has been shown, it would be better to identify any subgroups of SSc patients that are particularly susceptible to smoking. Because it has been shown that different patterns of pulmonary involvement are seen in different subtypes of SSc [36]. On the other hand, due to the effect of “a healthy smoker”, there is a need to clarify the mechanisms of smoking-induced lung disease in SSc. 4.4 Other organ impairment Smoking has been reported to worsen acid reflux in gastrointestinal disease [37]. According to the report, the GI tract is also involved in around 90% of all patients with SSc. But it is unclear whether the gastrointestinal involvement are also influenced by smoking in SSc. Hudson et al [12] recently explored the association between smoking and various clinical problems in SSc. They found that smoking significantly increased the risk of GI symptoms and poor appetite. Moreover, in addition to above problems, the relationship between smoking and other organ problems have also been explored in recent years. For example, one study [38] from Canadian was attempted to determine whether cigarette smoking worsens the sleep disruption in patients with SSc, results showed that smoking were associated with sleep scores in bivariate analyses. Beyond that, Thombs and colleagues [39] used a
hierarchical multiple linear regression to assess multivariable associations between demographic (step 1), socioeconomic (step 2), global disease (step 3), specific disease and life-style factors (step 4), and depression and pain (step 5) with fatigue (SF-36 vitality subscale scores) in SSc, and found that higher fatigue was significantly associated with current smoking (standardized β=0.08, P =0.018). On the other hand, another study [40] have demonstrated that survival was decreased in past or present smokers
compared with those who had never smoked. Cox proportional hazards regression
revealed that the significant hazard ratio (HR) of 1.53 (95% CI 1.02–2.30, P =0.038) persisted after stratification by sex and adjustment for age at disease onset. This risk was higher in current smokers (HR 1.93 [95% CI 1.09–3.44]) as compared to those who had stopped smoking (HR 1.28 [95% CI 0.81–2.03]). Further, survival in smokers decreased with increasing pack-years in those with a history of ≥40 pack-years, demonstrating an HR of 2.21 (95% CI 1.33–3.66, P = 0.002), after adjustment for sex and age at disease onset. The effect of smoking on the clinical symptoms in SSc patients is very complicated, because such patients are likely to have more severe disease, this is likely to influence the relationship between cigarette smoking and these clinical symptoms. It is also important to consider whether patients with more severe disease started smoking after they had an organ involvement. Thus, further investigation on the true pathogenesis and nature of smoking in systemic sclerosis should be performed. 5. Potential mechanisms of smoking and SSc Although the biologic pathway through which cigarette smoking acts to increase the risk of SSc is not completely understood, previous studies have had some review articles [41, 42] to explain in detail the biologic effect of smoking on the development of autoimmune rheumatic diseases. Here, we make a detailed introduction to these mechanisms. (Fig.1)
First, cigarette smoke contains thousands of chemicals that have cytotoxic, mutagenic, carcinogenic, or antigenic properties [2]. The products of combustion can be divided into gaseous and particulate components, both of which contain extremely high concentrations of free radicals and cigarette smoke activates endogenous sources of free radicals as well. Reactive oxidative species (ROS) produced from the metabolism of constituents of tobacco smoke and free radicals can interact with DNA, and could cause genetic mutations [18]. Indeed, a significantly higher risk of anti-dsDNA seropositivity in current smokers with SLE than in never smokers has been demonstrated. For example, smoke, by provoking oxidative stress, may contribute to lupus disease by dysregulating DNA demethylation, upregulating immune genes thereby leading to autoreactivity [43]. This, therefore, might have a role in the development of autoimmune disease. Second, combustion is an important step that produces reactive oxidative substances (ROS), which activate epithelial cell intracellular signaling cascades that lead to inflammatory gene activation [e.g., IL-8 and tumor necrosis factor-alpha (TNFα)] [44] , therefore, initiate inflammatory processes. Third, there is increasing evidence that nicotine, a major component in cigarette smoke, may have an immunosuppressive effect [42]. It induces abnormalities in T cells, reduces the activity of natural killer cells and decreases serum levels of IgM and IgG. These modulations in both cellular and humoral immunity might contribute to the induction of autoimmune processes. Fourth, cigarette smoking has anti-estrogenic effects through the formation of inactive 2-hydroxy catechol estrogens [18]. Estrogens can affect the Thl/Th2 immune balance and estrogens have either pro- or anti-inflammatory actions depending on the estrogen/androgen balance [45]. Through the modulation of hormonal balance, smoking might, therefore, enhance inflammatory processes.
In summary, the mechanisms by which smoking affects autoimmune diseases are multiple and complex. Continued exploration of how cigarette smoking acts as a trigger of autoimmunity is necessary. Animal models and basic research into the biologic effects of the constituents of cigarette smoke, as well as ongoing large cohort studies will advance our understanding of disease mechanisms. And the search for gene-environment interactions involving smoking and other environmental exposures should proceed in parallel.
6. Discussion This is a comprehensive study investigating the effect of smoking on multiple outcomes in patients with SSc. Although previous results do not convincingly support that patients with SSc are at a significantly increased risk for developing smoking, various studies have show convincingly that smoking was associated with a significant negative impact on skin, vascular, gastrointestinal, and respiratory outcomes in SSc [5, 11, 12, 33, 34, 38, 46, 47], and that these effects might be long-lasting (e.g., respiratory outcomes). Moreover, there are epidemiology and basic studies shown that smoking can affect these symptoms by different mechanisms (See Figure 1). Therefore, we believe that smoking cessation could have a protective effect against the development of SSc and these patients should be recommended to abstain from smoking. Unfortunately, epidemiological data often are obtained from retrospective studies and underpowered case-control studies, which often suffer from some shortcomings in methodology. As we all know, SSc is a rare disease, with a prevalence in the North America between 3 and 24 per 100,000 population [48]. It is therefore difficult to recruit large numbers of patients for investigation, so some studies used a convenience sample of SSc patients enrolled in the Registration System, but patients in the Registry may overrepresent relatively healthy SSc patients, as opposed to patients with severe SSc
who may have been too sick to participate or died early in their disease course. In addition, because of the diversity of study designs, control populations, patient populations, and the methodology used to determine smoking history, the results will be contradictory between different researches. For example, it may be that persons with one established chronic illness are more likely to be aware of (or to report) comorbidity due to the fact that they have more contact with the medical system than persons in the general population, which might create a ‘detection’ bias. So it is clear that failure to account for these biases may lead to under- or overestimates of the association between smoking and disease outcomes. Therefore, there are so many precautions need to be considered in future studies. First, it is better to use unified measuring scale (for example, the CSI) to determine smoking history in epidemiological studies. And future studies in SSc should also aim to gather a larger number of moderate to heavy smokers. Second, it is very important that selecting reasonably the patients and control groups and match out those suspected confounding factors (e.g. drinking or along with other diseases) in future studies of the relationship between smoking and SSc. Third, how genetics and environmental factors interact in SSc pathogenesis and development? The interaction of smoking (as an environmental factor) with genetic susceptibility might further complicate the understanding of these mechanisms. So it is worthwhile to study smoking interactions with genetic susceptibility and other exposures such as virus infection which could lead to dangerous negative interactions in the onset and progression of the disease. And last, the mechanism of smoking on SSc risk may be quite complicated. Therefore, larger prospective longitudinal clinical and epidemiological studies are necessary, preferably complemented
by specific animal model studies as well as parallel laboratory testing to better understand the role of smoking in SSc.
7. Conclusion In conclusion, this review suggested that smoking increased the risk of skin, vascular, gastrointestinal, and respiratory outcomes in SSc. There is a need, therefore, those SSc patients should prioritize smoking cessation as part of the management of the disease. In addition, the mechanisms by which smoking affects autoimmune rheumatic diseases are multiple and complex. Further epidemiological data and animal studies are needed to done in order to fully appreciate the role of smoking in these diseases. Acknowledgements This work was partly supported by grants from the Anhui Provincial Laboratory of Population Health & Major Disease Screening and Diagnosis, the Key Project of the Education Department of Anhui Province Natural Science Research. Conflict of interest The authors declare no conflicts of interest. Reference 1.
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Highlights
1. This is a comprehensive study investigating the effect of smoking on multiple outcomes in patients with SSc. 2. Smoking was associated with a significant negative impact on digital ulcers, pulmonary function, and lung cancer in SSc.3. Cigarette smoking can interact with DNA and could cause genetic mutations. It can also cause inflammatory gene activation. In addition, cigarette smoking has also many other adverse effects on the onset of SSc, such as causing inflammation and impairing immune functiont; Finally, smoking has anti-estrogenic effects through the formation of inactive 2-hydroxy catechol estrogens.
Cigarette Smoking
T /B cells NK cell、 、 Macrophages activity
Gene-smoking interaction
Inactive 2-hydroxy catechol estrogens
Inflammatory gene activation
Alteraction of cytokines
(IL-1、 、 IL-8、 、 TNFα)
IgG anti-dsDNA
Anti-estrogenic
antibodies
effects
IL-6、 、 CRP
Inflammatory
Immune dysregulation
SSc
Fig 1 Cigarette smoking affects the SSc in diverse ways. Cigarette smoking can interact with DNA and could cause genetic mutations. It can also cause inflammatory gene activation (eg. IL-1 and IL-8). In addition, cigarette smoking has also many other adverse effects on the onset of SSc, such as causing inflammation and impairing immune functiont; Finally, smoking has anti-estrogenic effects through the formation of inactive 2-hydroxy catechol estrogens. Abbreviations: CRP, C-reactive protein; TNFα , tumor necrosis factor.
Table 1
The association between cigarette smoking and various clinical symptoms of SSc patients. Smoke First Type of study and methods Patients (past/present) Outcomes author,year (%) OR for SSc in smokers vs never sm Chaudhary Cross-sectional study; 1379 43/42.5 2011 621 cases and 1228 controls 0.839- 1.240). OR for SSc in smokers vs never sm Atteritano Case-Control study; 54 31.5/29.6 2013 54 cases and 54 controls 0.481- 2.475). OR for SSc in smokers vs never sm Pischon Case-Control study; 58 53.4/40.4 2016 58 cases and 52 controls 0.823- 3.766). Cross-sectional study; Smoking was significantly associated Caramaschi 29 digital ulcers and 56 85 34.5/8.9 SSc. 2009 without digital ulcers P=0.003, OR: 2.46 (1.45- 4.15) Cross-sectional study; Smoking was not a risk factor for skin Alivernini 34 skin ulcers and 96 130 8.8/14.6 P=0.274, OR: 0.64(0.22- 1.88 ) 2009 without digital ulcers Khimdas Smoking was not a risk factor for digi Cross-sectional study; 938 71.6 2011 P=0.909, OR:0.984 Current smokers are 3-4 times never-smokers to incur digital vascula Harrison Cross-sectional study; 101 57.4 OR: 3.8(1.1-12.9) for Admission for I 2002 OR: 4.5 (1.1-18.3) for Digital Debride OR: 3.4 (0.8-15.1) for Digital Amputa Smoking was significantly associa Genevie`ve Cross-sectional study; 606 57.9 skin disease in SSc. Gyger,2012 P=0.0029, OR:0.84(0.75-0.95) Cross-sectional study; Smoking was not associated with pulm Broholm 30 pulmonary fibrosis and 155 43.3/55.2 P=0.246, OR:0.68(0.36-1.30) 2008 125 non pulmonary fibrosis Smoking was significantly associate Nested case-control study; Freemer SSc patients. 20 lung cancer and 41 61 90.0/56.1 2007 P=0.016, OR=7.04 ( 1.44-34.39 ) gender-matched controls The smokers had a significantly highe Silvia Cross-sectional study; 46 26.1 2008 percentage of predicted (P = 0.036, P= Smoking appears to have an additiv Cross-sectional study; Steen pulmonary function in SSc patients.(P 137 smoking SSc and 165 302 45.4 1985 OR for Restrictive 1.908 (95% CI: 1.0 nonsmoking patients OR for Obstructive 4.387 (95% CI: 2. Higher obstructive and restrictive lun TERRY Cross-sectional study; 203 23.6 smokers compared with the 2007 P=0.062, respectively) Kang Cross-sectional study; Smoking was not associated with canc 112 11.1/3.7 2009 9 SSc with cancer and 103 P= 0.326,OR: 0.304(0.028-3.273)
Thombs 2009 Hudson 2011 BRETT D.2009 Milette 2011 Vemulapalli 2016 Santosa 2016 Hissaria 2011
without cancer Cross-sectional study; 81abnormal Pap test and 239 without abnormal Pap test
320
25.9/13.4
Cross-sectional study;
606
57.9
Cross-sectional study;
659
15.9
Cross-sectional study;
70
15.7
300
47.4/32.9
349
12.3
786
47.7
Cross-sectional study; 133 SSc with diastolic dysfunction and 167 controls Cohort study; systemic sclerosis cohort Singapore (SCORE) Cohort study; South Australian Scleroderma Register (SASR)
Smoking was significantly associated cancer screening (Pap test) in SSc pati P=0.008, OR:2.43(1.23, 4.78)
The number of GI symptoms, poor a showed statistical significant smoking.(P=0.03, P=0.03, P=0.01, res Higher fatigue was significantly a smoking ( P =0.018). Sleep disruption was associated with bivariate analyses. Smoking was significantly assoc dysfunction in SSc patients. P=0.011 , OR:1.833 ( 1.147-2.930)
Multivariate analysis showed that sm was independ CI: 1.5-10.6] mortality.(P=0.016) Cox proportional hazards regressi significant HR of 1.53 (95% CI 1.02–2.30, P= 0.0