Effects of tobacco smoke on immunity, inflammation and autoimmunity

Journal of Autoimmunity 34 (2010) J258eJ265

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Journal of Autoimmunity journal homepage: www.elsevier.com/locate/jautimm

Effects of tobacco smoke on immunity, inflammation and autoimmunity Yoav Arnson a, b, Yehuda Shoenfeld c, Howard Amital a, b, * a

Department of Medicine D, Meir Medical Center, Kfar Saba, Israel Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel c Department of Medicine B and Center for Autoimmune Diseases, and Tel Aviv University, Sackler Faculty of Medicine, Sheba Medical Center, Tel Hashomer, Israel b

a b s t r a c t Keywords: Cigarette smoke Nicotine Inflammation Immunosupression Autoimmunity

Smoking is a central factor in many pathological conditions. Its role in neoplasm, lung and cardiovascular diseases has been well established for years. However it is less acknowledged the cigarette smoking affects both the innate and adoptive immune arms. Cigarette smoke was shown to augment the production of numerous pro-inflammatory cytokines such as TNF-a, IL-1, IL-6, IL-8 GM-CSF and to decrease the levels of anti-inflammatory cytokines such as IL-10. Tobacco smoke via multiple mechanisms leads to elevated IgE concentrations and to the subsequent development of atopic diseases and asthma. Cigarette smoke has also been shown activate in many ways macrophage and dendritic cell activity. While it is better evident how cigarette smoke evokes airway diseases more mechanisms are being revealed linking this social hazard to autoimmune disorders, for instance via the production of antibodies recognizing citrullinated proteins in rheumatoid arthritis or by the elevation of anti-dsDNA titers in systemic lupus erythematosus. The current review underlines the importance of smoking prevention and eradication not only in respiratory disorders but also in autoimmune conditions as well. Ó 2009 Elsevier Ltd. All rights reserved.

Tobacco smoking is one of the most potent and prevalent addictive habits, influencing the behavior of human beings for over four centuries. Tobacco smoke affects multiple organ systems and results in numerous tobacco-induced diseases. The well-known health risks of tobacco smoking especially relate to the respiratory tract and the cardiovascular system. Smoking influences the immune system in many ways. Many systemic chronic conditions are likely to result from the indirect consequences of continual exposure to the chemicals in cigarette smoke, resulting in inflammatory reactions to the oxidative stress and effects of smoking. In addition, smokers have increased vulnerability to several infections and are predisposed to allergic airway diseases [1] (Fig. 1).

particles. The smoker inhales the nicotine-enriched aerosol, with particle size in the micron range, permitting efficient alveolar deposition and rapid absorption in the systemic blood. Burning cigarettes produce as much as 6000 different components in addition to nicotine, including polycyclic aromatic hydrocarbons, tobacco glycoprotein and some metals, many of which are known to be antigenic, cytotoxic, mutagenic, or carcinogenic, and most of them are generated by the burning tobacco. Chronic exposure of rats to the vapor phase of cigarette smoke does not lead to significant changes in the immune response, indicating that immunosuppressive properties of cigarette smoke are mainly associated with the particulate phase of cigarette smoke [2].

1. Cigarette smoke composition The burning of tobacco at the tip of the cigarette heats the air drawn through it. The heated air then passes through unburned tobacco causing nicotine and other components to evaporate. As the air later cools, some of these components condense into smoke

* Corresponding author at: Howard Amital, Department of Medicine D, Meir Medical Center, Tshernichovsky 59, Kfar Saba 95847 Israel. Tel.: þ972 9 7472598; fax: þ972 9 7471313. E-mail addresses: [email protected], [email protected] (H. Amital). 0896-8411/$ e see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.jaut.2009.12.003

2. The effects of smoking on the immune system Cigarette smoking affects both cell-mediated and humoral immune responses (Table 1). Studies show that maternal smoking alters both the adaptive and innate immune arms of newborns [3]. Smoking is associated with both release and inhibition of proinflammatory and anti-inflammatory mediators. A large network of pulmonary and systemic cytokines is involved in chronic inflammation of smokers. Cigarette smoke induces the release of TNF-a, TNFa receptors, interleukin (IL)-1, IL-6, IL-8 and granulocyte-macrophage

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Fig. 1. Cigarette smoking affects the immune system in diverse ways, both increasing inflammatory allergic and autoimmune reactions, and decreasing systemic activity against infections.

colony-stimulating factor (GM-CSF) [4,5]. On the other hand, smoking has also been associated with decreased IL-6 production through Toll-like receptors (TLR)-2 and 9, decreased IL-10 production via TLR-2 activation and also decreased IL-1b, IL-2, TNF-a, and IFN-g production by mononuclear cells [6]. The inhibitory effects of cigarette smoking have been attributed to nicotine, hydroquinone (the phenolic compound in cigarette tar) and to carbon monoxide in the smoke. Nicotine had suppressive effect on IL-6 inflammatory cytokine levels [7]. It can inhibit IL-10 production. That effect is utilized for treatment with nicotine

patches in patients with inflammatory bowel disease [8]. IL-8 is a potent leukocyte chemotactic factor, specific for neutrophils. In studies performed in patients suffering from Behçet's disease, nicotine was observed to inhibit endothelial cell release of IL-8 [9]. Some of the inhibitory effects of nicotine have been attributed to its effect on the a7 nicotinic actylcholine receptor found in macrophages, T-cells and B cells [10]. Activation of this receptor has been shown to reduce production of the pro-inflammatory cytokines TNF-a, IL-1b and IL-6, suppressing Th1 and Th17 reactions, but not Th2 reactions [10].

Table 1 The mixed effects of smoking and nicotine exposure on the function of the immune system. Immuno-suppressive effects Effects on dentritic cells and antigen-presenting activity Suppression of dendritic cell maturation and cytokine release. Action on neutrophils and macrophages Suppression neutrophil-mediated inflammatory actions. Depressed PMNs migration and chemotaxis. Reduced macrophage activity against intracellular organisms. Action on the T-cell lymphocyte population. Nicotine inhibits the antibody-forming cell response, impairs antigen-mediated signaling in T-cells and induces T cell anergy.

Pro-inflammatory effects Activation of dendritic cell-mediated adaptive immunity. Increased circulatory levels of PMN.

Polyphenol-rich glycoprotein stimulates the proliferation of peripheral T-lymphocytes. Increased circulatory levels of T-lymphocytes. Abnormal CD4(þ)/CD8(þ) ratio. Favored activity of the Th2 allergic pathway

Action on B cell lymphocyte population Augmentation of auto-reactive B cells. Effects on humoral immunity Reduced circulating levels of immuno-globulins. Action on inflammatory markers and mediators: Inhibition of IL-1b, IL-2, Il-10, TNF-a, and IFN-g release. Inhibition of endothelial cell release of IL-8. Other general non-specific mechanisms: Attenuation of IFN signaling

Chronic smoking increases levels of acute phase proteins and pro-inflammatory cytokines, especially TNF-a, TNF-a receptors and IL-6. Exposure and release of autoantibodies: Release of intracellular antigens via tissue hypoxia or toxin-mediated cellular necrosis. Increased concentration of free radicals, which interact with DNA.

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Endotoxin (lipopolysaccharides, LPS) is one of the most potent inflammatory agents known. Tobacco smoke increases endotoxin exposure by far, more than hundred times compared with nonsmoking environment; these high levels could contribute to an elevated IgE and the subsequent development of atopic diseases and asthma. CD14 is the receptor for LPS and other bacterial wallderived components. There is an interaction between asthma severity and levels of CD14 and IgE [11]. The early exposure to endotoxin, both prenatal and postnatal, increases the risk of IgE sensitization to indoor inhalant and, in particular, food allergens and subsequently may lead to atopy and airway hyperresponsiveness [12]. The net effect of cigarette smoking on polymorphonuclear neutrophils (PMN) is elevation of the PMN count with and reduction of their functionality. The systemic inflammatory response triggered by exposure to cigarette smoke is characterized by the stimulation of the hematopoietic system, specifically the bone marrow, which results in the release of leukocytes and platelets into the circulation, ascribed to the relative increase of PMN counts in the circulation of smokers [13]. Smokers have a higher average number of circulating PMNs by up to 30% compared with non-smokers which is primarily caused by the nicotine induced secretion of catecholamines [14]. Van-Eeden and Hogg [15] found that PMNs from long-term smokers have phenotypic changes indicating bone marrow stimulation, such as increase in band cell counts, higher levels of L-selectin, and increased myeloperoxidase content. Tell et al. [16] showed the same relationship between cigarette smoking and increased leukocyte count in adolescents, suggesting a rapid effect of cigarette smoking on white blood cell count unrelated to the chronicity of smoking and its related medical conditions. The abundance of PMN in the airways of smokers enhances proteolitic enzyme activity such as neutrophil elastase, cathepsin G, and protease-3. Neutrophil proteases stimulate mucin release by goblet cells. They also have a destructive effect on ciliated cells and are capable of destroying the extracellular matrix. Nicotine has been shown to inhibit formation of free oxygen radicals in PMN. Thus, it is likely that nicotine has also the capacity to suppress several neutrophil-mediated inflammatory actions. PMN from the peripheral blood of smokers also exhibit depressed migration and chemotaxis compared with PMN from non-smokers [17]. Macrophages are the main lung cell population which serves as the first line of cellular defense against pollutants due to their antigen-presenting function and phagocytic properties. Cigarette smoke particles (the main component of particles is kaolinit) are visible in a light microscope in the cytoplasm of alveolar macrophages, even after a short period of tobacco use and they persist up to 2 years following smoking cessation [18]. Chronic smoke exposure causes an influx of alveolar macrophages into the airways lumen of smokers [19]. Apart from changes in the morphology and the number of alveolar macrophages, impaired function of these cells has been observed in smokers. In general, macrophages obtained from tobacco smokers are less mature, have elevated expression of CD14 (monocyte marker), have a condense cytoplasm, and are hyperdense. Macrophages from the lungs of smokers have a greater inhibitory effect on lymphocyte proliferation and natural killer (NK) cells than macrophages from the lungs of non-smokers. They also express a selective functional deficiency in their ability to kill intracellular bacteria [20]. Cigarette smokers have been shown to have an increased total number of circulating T-lymphocytes [21]. The differentiation of T-cells is a matter of controversy. Several investigators have reported a decrease in CD4(þ) cells (T-helper cells), impaired CD4 (þ) T-cell function and an increase in CD8(þ) cells (T-suppressor

cells) with a subsequent decrease in the CD4(þ)/CD8(þ) ratio in heavy smokers (Over 50 PY) [22]. In light smokers, under 50 PY, an increase in leukocyte count has been observed with a selective increase in CD4(þ) cells, resulting in a significant increase in the CD4(þ)/CD8(þ) ratio [23]. Two to four years after smoking cessation, the increase in CD4 (þ) cells disappeared [24]. Bronchoalveolar lavage studies have demonstrated a marked decrease in the percentage and absolute number of CD4 (þ) cells, and an increase in CD8 (þ) cells in moderate smokers (average 14 PY), suggesting the circulatory lymphocyte subpopulations follow alveolar changes [25]. TLRs are essential for proper innate responses against microbes as well as for regulatory pathways inhibiting the allergic immune responses. TLRs are found on many cells involved in immediate host defense including antigen-presenting cells (APCs) and CD4 (þ)/CD25(þ) T-regulatory cells. Newborns of smoking mothers may have altered signaling through TLRs. Maternal smoking in pregnancy resulted in a diminished innate production of antigen-presenting cell (APC) cytokines, as well as an impaired response to TLR ligands [10]. A weak Th1 stimulation pathway could favor the development of Th2 allergic diseases. Accordingly, epidemiologic studies suggest that the incidence of hypersensitivity pneumonitis, a Th1-mediated hypersensitivity reaction to inhaled allergens, is rare in cigarette smokers [2]. Cigarette smoke exposure has been shown to inhibit the function of circulatory dendritic cells (DC), therefore specifically inhibiting key Th1 cytokine production and favoring development of Th2 responses. Smoke exposure has been shown to diminish the priming capacities of DC's, reduce endocytic and phagocytic activities, reduce the ability to stimulate Ag-presenting cell-dependent T-cell responses and reduce secretion of IL-10, IL-12 and co-stimulatory molecules from mature DC's [26]. It must be noted that some research groups reported that nicotine dose dependently enhanced DC co-stimulatory molecule expression, enhanced IL-12 and IL-10 release, and augmented the T-cell priming ability of DCs [27]. The ability of DC's to generate Th1 or Th2 immunity is regulated by many factors, including antigen type and dose, the level of co-stimulatory molecules expressed, the presence of polarizing cytokines and other mediators, and the presence of innate receptor stimulants at the time of antigen exposure. Chronic cigarette smokers display a characteristic increase in the amount of Langerhans cells, a subtype of myeloid DCs, in the airways [28]. Airway DCs of smokers display an increased expression of the co-stimulatory molecules CD80 and CD86, but a reduced expression of the lymph node homing receptor CCR7. These findings led to the hypothesis that DCs of smokers might have an increased ability to induce T-cell responses, but a reduced ability to migrate to draining lymph nodes. Several studies have found that smokers had serum immunoglobulin levels (IgA, IgG, and IgM) up to 10e20% lower than those of non-smokers [29]. Smokers also exhibit elevated levels of circulating IgE [30]. Higher serum levels of IgE in smokers do not correlate with increased skin-test reactivity, and cigarette smokers exhibit significantly lower skin-test reactivity for a given value of IgE than non-smokers. Chronic exposure of rats to nicotine inhibits the antibody-forming cell response, impairs antigen-mediated signaling in T-cells and induces T cell anergy [31]. 3. Smoking, chronic obstructive pulmonary disease, allergies and asthma Complex geneeenvironmental interactions play a key role in the development of asthma and rhinitis. Some recognized factors are early-life sensitization to aeroallergens, presence of atopic dermatitis or allergic rhinitis, early lower respiratory tract infections with

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respiratory syncytial virus and potentially infections with other viruses as well. Maternal smoking during pregnancy and children's exposure to environmental tobacco smoke are among the nonallergic factors associated with an increased risk for development of persistent asthma, rhinitis or both [32]. Infants of mothers who smoke have reduced respiratory function and are more likely to develop wheezing. A recent metaanalysis explored the relationship between tobacco exposure and the induction of childhood asthma. The significant reported relative risk (RR) for secondhand smoking and ever, current and incident asthma were 1.48 (95% confidence interval (CI) 1.32e1.65), 1.25 (95% CI 1.21e1.30) and 1.21 (95% CI 1.03e1.36), respectively [33]. In a cross-sectional study conducted on 6794 children smoking exposure was associated with increased risks of current symptoms of rhinitis [prevalence ratio (PR) 1.23; 95% CI 1.01e1.50] and rhinoconjunctivitis (PR 1.79; 95% CI 1.26e2.54). A higher prevalence of wheeze and doctor-diagnosed asthma was also found [34]. There is strong evidence that active smoking is a risk factor for the presence and severity of asthmatic symptoms, and for the development of asthma in adolescence and adulthood [35]. A doseresponse association was found between exposure to tobacco and risk of new-onset asthma, when smoking 1e10 pack-years had an OR of 2.05 (95% CI 0.99e4.27), 11e20 pack-years had an OR of 3.71 (95% CI 1.77e7.78) and 21 or more pack-years had an OR of 5.05 (95% CI 1.93e13.20) [36]. Smokers with asthma were found do have a reduced numbers of CD83 (þ) mature DCs in their bronchial mucosa as compared with either never-smoker patients with asthma or healthy never-smokers [37]. This alteration is accompanied by a significant reduction of B lymphocytes and a trend toward decreased numbers of cells expressing the protein for the Th1 cytokine IFN-g. Loss of DCs might also alter the balance of inflammatory cell phenotypes, resulting in a pattern more similar to that of chronic obstructive pulmonary disease and one that is less responsive to steroid treatment [38]. Chronic obstructive pulmonary disease (COPD) is a major worldwide medical problem, resulting in millions of deaths annually, and inestimable health care expenditures and productivity losses [39]. COPD is associated with autoantibodies that have avidity against pulmonary airway epithelial and, perhaps somewhat less frequently, pulmonary endothelial cells. Long-term exposure to tobacco smoke is the primary risk factor for COPD. Recent evidence supports a likely role of adaptive immune responses in progression of COPD, including correlations of disease severity with characteristics of intrapulmonary and peripheral T-cells [40].

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Tobacco smoking modulates the proliferation and death pathways of lymphocytes, it induces new epitopes by either directly oxidizing existing proteins or indirectly by interfering with the clearance of apoptotic cells, exposing anatomically sequestered intracellular antigens to the immune system and up-regulating the population of antigen-presenting cells in the lungs thus amplifying the capacity to process new antigens [41]. 4. The autoimmune hazards of smoking The etiopathogenesis of autoimmune disorders are multifactorial in nature. Environmental factors such as exposure to infectious agents, vaccines, medications, stress, and smoking are thought to predispose certain individuals to the development of autoimmune diseases [42]. Existing studies present conflicting evidence regarding the role of cigarette smoking in the development and severity of autoimmune diseases. Studies discussing this association vary widely in their designs, population sizes, definitions of duration and extent of smoking, and with the methods used to distinguish the effects of cigarette smoking from other predisposing socio-economic and environmental confounders. Although facing limitations, strong evidence link smoking to the presence of rheumatoid arthritis (RA), systemic lupus erythematous (SLE), Graves' disease, and primary biliary cirrhosis (PBC) [43] (Table 2). No clearly described, historic occurrences of RA are mentioned in the ancient and medieval literature, indicating a possible association of the emergence of RA with tobacco exposure, following its discovery in the Americas. Although the biological pathway through which cigarette smoking acts to increase the prevalence of autoimmune phenomena is not yet fully characterized, many potential mechanisms have been proposed. It is possible that cigarette smoke leads to a release of intracellular antigens via tissue hypoxia or toxinmediated cellular necrosis, thereby overwhelming the scavenging capacity of the immune system, which ultimately precipitates an immune reaction in susceptible individuals. Cigarette smoke byproducts can augment auto-reactive B cells [44]. Polyphenol-rich glycoprotein is isolated from tobacco leaves and is present in cigarette smoke. It has been shown to stimulate the proliferation of peripheral T-lymphocytes [45]. Cigarette smoke also contains extremely high concentrations of free radicals. In addition, it can increase the generation and activation of endogenous free radicals. These toxins interact with DNA

Table 2 Influence of smoking on prevalence and expression of autoimmune conditions. Disease Autoimmune conditions exacerbated by smoking Rheumatoid arthritis Systemic lupus erythematous Graves' hyperthyroidism Crohn's disease Goodpasture's syndrome Thromboangiitis obliterans (Buerger's disease) Primary biliary cirrhosis Systemic sclerosis Multiple sclerosis Firbomyalgia Autoimmune conditions improved by smoking Ulcerative colitis Behçet's disease and aphtous stomatitis

Manifestations of smoking Increased prevalence in smokers, mostly men and long-term smokers. Higher rate of rheumatoid nodules and multiple joint involvements. Lower response to treatment Slightly elevated risk for present smokers. Elevated titers of anti-dsDNA in current and past smokers. Higher disease prevalence in past and current smokers, increased rates of Graves' ophthalmopathy Increased prevalence in past and current smokers. Higher prevalence of ileal disease and a lower prevalence of colonic involvement in smokers. Greater likelihood for complicated disease. Smoking predisposes to pulmonary hemorrhage regardless of anti-GBM titers. Prevalent almost entirely in young, male smokers. Increased disease prevalence in smokers Higher rates of digital ischemia in smokers Higher incidence of disease in smoking women, worse clinical progression. More pain, numbness, disease severity, and functional difficulties in smokers Reduced risk in current smokers. Slightly elevated risk in former smokers. More benign disease course in smokers. Symptom exacerbating during smoking cessation. Fewer oral aphthae in smokers.

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and may cause genetic mutations and elicit gene activation that leads to autoimmune diseases [46]. Another proposed mechanism is via the anti-estrogenic effects of smoking. Estrogen is known for its moderating effects on diseases such as RA and many pregnant women enjoy symptomatic relief during pregnancy. Through modulation of the hormonal balance, smoking might enhance inflammatory processes. 5. Smoking and RA RA is a common rheumatologic condition affecting approximately 1% of the adult population in the United States [47]. Several reports support the view that RA is probably a clinical syndrome consisting of at least two distinct diseases defined by the presence or absence of autoantibodies recognizing citrullinated proteins (ACPA). As mentioned earlier, RA is one of the classical disorders that result from the interaction between environmental and predisposing genetic factors. Associations have been suggested with diet, coffee intake, alcohol and body mass index [48]. The only well established risk factor is cigarette smoking. The first association between RA and smoking was suggested by Vessey et al. [49] in the 1980s, who unexpectedly documented a marked increase in hospital admissions due to RA in smokers. Several studies since then have linked smoking with the risk of RA. Prospective case-control studies have shown that cigarette smoking is also gender-related concerning its capacity to facilitate the development of RA, being higher in men than women [50]. However, prospective cohort studies have demonstrated that tobacco exposure also increases the risk of RA in women. For example, in the Nurses' Health Study cohort, the HR of developing RA during the premenopausal and postmenopausal years in the cohort for ever-smokers was 1.48 and 1.53, respectively [51]. The risk of RA was significantly elevated with 10 pack-years or more of smoking and increased linearly with increasing pack-years (HR 1.5e2). Importantly, the risk of RA remained substantially elevated until 10e20 years after smoking ceased [52]. A recently published meta-analysis reviewing this association indicated that the risk for male smokers of developing RA is about twice that of male nonsmokers. For females, the risk for smokers is about 1.3 times greater than that of non-smokers. However, for heavy smokers (twenty pack-years of smoking or more), the risk was equally high for females and males [53]. A significant association was found between smoking and the presence of ACPA in a large number of studies [54]. Overall, the risk for ACPA positively increased with the number of pack-years and was particularly important for a cumulative dose of over 20 packyears (OR ranging from 1.65 to 4.2). In a cohort of ACPA-positive RA patients, Immunoglobulin (Ig) A and IgM ACPA were more frequently detected in RA patients who were smokers than in nonsmokers (OR 2.8 and 1.8, respectively) [55]. Certain HLA-DRB1 *01 (HLA-DR1) and HLA-DRB1*04 (HLA-DR4) alleles, also known as “shared epitopes”, have been associated with susceptibility to RA [56]. Shared epitopes are probably the primary risk factor for increased ACPA production in RA [57]. A high risk for the development of ACPA-positive RA was observed in patients carrying one or two shared epitope alleles [58]. In shared epitope positive patients, smoking was not only associated with positive ACPA, but also with absolute serum anti-CCP levels. RA severity can be defined according to the degree of structural damage and to the occurrence of extra-articular manifestations or cardiovascular involvement. The presence of rheumatoid factor (RF) and ACPA is known to be associated with a more significant radiological progression and structural damage. A two-step model has been suggested for the pathogenesis of this subset of ACPApositive RA patients [59]. Long-term exposure to tobacco smoke

would induce mechanisms that accelerate the citrullination of autoantigens present in the lungs, because the chronic inflammatory process is responsible for diminution of arginine to citrulline. In this regard, individuals who are smokers display higher citrullination in cells obtained from bronchoalveolar lavage. However, citrullination is not specific to RA and might occur in other types of arthritis. Thus, the production of ACPA antibodies requires a specific genetic background. The immune response to citrullinated proteins would be preferentially induced in individuals carrying the HLA-DR shared epitope genes. Smokers with RA have a disease characterized by a greater proportion of auto-antibody positivity [60]. Smoking seems to contribute significantly to the occurrence of extra-articular manifestations of RA in European, African-American, and Korean populations. Several studies have yielded that smokers, especially RF-positive RA smokers, have an increased risk of rheumatoid nodules [61]. Smoking status has been associated with treatment responsiveness. Patients with RA who smoke show a greater need for disease modifying anti-rheumatic drugs (DMARDs), with non-smokers and patients with fewer than 20 pack-years having a significantly higher probability of improvement than heavy smokers [62]. RA patients with a history of smoking were found to show a poor response to treatment with TNF antagonists. Response failure was associated with the intensity of previous smoking, irrespective of smoking status at initiation of anti-TNF therapy [63]. In a recent report, smoking was associated with non-response to both methotrexate (MTX) and anti-TNF treatment. For MTX treatment, 40% of current smokers and 28% of never-smokers were non-responders (OR 1.8, 95% CI 1.2e2.7). However, no clear dose-response effect was observed between the number of pack-years and response. For antiTNF therapy, 40% of current smokers and 25% of never-smokers were non-responders (OR 2.0 [95% CI 1.1e3.7]). When the patients were grouped according to number of pack-years of cigarette smoking into 0, 1-15, 16-30 and>30 pack-years; the frequency of nonresponse to anti-TNF therapy was 25%, 31%, 40%, and 43%, respectively (OR, 1.3, 2.0 and 2.3, respectively) [64].

6. Smoking and SLE Cigarette smoking has been proposed to be a trigger for both development and severity of SLE and many studies have examined that correlation with mixed results [65]. In a prospective study of 64,000 African-American women, the RR for SLE incidence in current and past smokers was 1.6, with an increased risk in women who started smoking before the age of 19 [66]. Costenbader et al. [67] performed a meta-analysis of seven case-control studies and two large cohort studies and concluded that smoking has a mild, yet significant contribution, elevating the risk for developing SLE with an OR of 1.50 (95% CI 1.09e2.08), with no increased risk for former smokers compared to non-smokers. In a large retrospective study, higher titers of anti-double-stranded DNA (dsDNA) were found in current and past smokers compared to non-smokers (OR 4.0 and 1.4, respectively) [68]. Ghaussy et al. [69] investigated the impact of smoking on disease activity in SLE patients. Current smokers demonstrated significantly higher SLE disease activity than former smokers and never-smokers. Current smokers have been reported to have more serious cutaneous involvement than former or never-smokers [70]. SLE patients who are current smokers were also found to suffer from more episodes of pleuritis and peritonitis and to express more neuropsychiatric symptoms [71]. Lupus nephritis did not appear to be related to tobacco exposure [72], although smoking has been associated with accelerated development of end-stage renal failure [73].

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Several studies have demonstrated a decreased response to anti-malarial therapy in patients suffering from cutaneous lupus erythematous [74].

7. Smoking and autoimmune thyroid diseases Smoking is a risk factor for the development of Graves' hyperthyroidism (GH) and even more so for Graves' ophthalmopathy [75]. A meta-analysis showed an odds ratio for GH of 3.30 (95% CI 2.09 to 5.22), based on data from eight studies among current smokers compared with persons who had never smoked [76]. The meta-analysis also showed that the odds ratio for Graves' ophthalmopathy among persons who had ever smoked was 4.40 (95% CI, 2.88 to 6.73). Among current smokers, the HR for GH increases with the intensity of smoking [77]. Cigarette smoking enhances the risk for progression of ophthalmopathy following radio-iodine therapy and decreases the efficacy of orbital radiation therapy and glucocorticoid therapy [78]. In an observational study, smoking cessation in Graves' patients was associated with a decreased risk for developing exophthalmos and diplopia [79]. The reason for the strong association of smoking with Graves' ophthalmopathy is largely unknown. Hypoxia may play a role, because fibroblasts show a significant increase in proliferation and glycosaminoglycan production when cultured under hypoxic conditions [80]. Thiocyanate, a major component of smoke, derived from hydrogen cyanide, leads to increased excretion of iodine, inhibits iodine uptake by the thyroid, competes with iodide in the organification process, and inhibits thyroid hormone synthesis [81].

8. Smoking and inflammatory bowel disease The link between smoking and inflammatory bowel disease (IBD) was first made in 1982 when Harries et al. [82] noticed that a low proportion of ulcerative colitis (UC) patients were smokers. The RR of developing Crohn's disease (CD) was reported to be 4.8 in those who smoked before disease onset, and 3.5 for those with a current smoking habit [83]. A meta-analysis conducted over twenty years ago found a pooled OR of 0.41 (95% CI 0.34e0.48) for current smokers to develop UC in compared with lifetime non-smokers. The effect of smoking seems to only postpone the event, as the RR for UC was also higher in former smokers (OR-1.64; 95% CI 1.36e1.98) [84]. UC usually runs a more benign disease course in smokers compared to non-smokers with fewer flare-ups, decreased hospitalization rates, less need for oral steroids, and lower colectomy rates [85]. An interesting link has been reported between smoking habits and the course of UC. Ever smoking was found to be associated with increased risk of CD development (OR, 1.61; 95% CI 1.27e2.03) [86]. Smoking also affects the disease course. Many studies report a higher prevalence of ileal disease and a lower prevalence of colonic involvement in smokers [87]. Smoking was associated more frequently with penetrating intestinal complications and greater likelihood to progress to complicated disease, as defined by development of strictures or fistulae and a higher relapse rate [88]. Treatment with nicotine was tested clinically in UC [89]. Initial trials showed the efficacy of nicotine delivered in transdermal patches in controlling active disease [44,45], but its failure to maintain remission. The reason behind the opposite effects of smoking observed in CD and UC remain obscure. Smokers with IBD have a significant reduction in mucosal cytokine levels, specifically, IL-1b and IL-8 in patients with UC, and IL-8 in patients with CD [90].

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9. Smoking and vasculitis syndromes Cigarette smoke exposure relates to pathological processes in blood vessel walls. Except for the atherosclerotic process associated with cigarette smoke, there are a few specific vasculitis syndromes related to smoking. Thromboangiitis obliterans (Buerger's disease) is a vasculitis in young, mostly male smokers that affects the small and medium-sized arteries and veins of the limbs. Discontinuation of smoking is the only proven definitive therapy. Various investigations have been carried out to identify an autoimmune mechanism responsible for Buerger's disease. Hypersensitivity to type I and III collagen associated with the presence of anti-collagen or anti-elastin antibodies [91] has been suggested. These abnormalities are considered to be non-specific and the pathological process underlying the disease is still unknown. Behçet's disease (BD) is a complex of signs and symptoms, with oral aphthae as the sine qua non finding. Smokers have been reported to exhibit oral aphthae less frequently than non-smokers, and during periods of smoking, patients with BD had fewer oral aphthae (both in number and frequency) compared to periods of abstinence [92]. The overall presence of aphtous stomatitis has also been observed to be higher in non-smokers than in smokers [93]. These effects are thought to result from the inhibitory effect of nicotine exposure on IL-8, and to some extent IL-6, which are pivotal pro-inflammatory agents in this disease [13]. Goodpasture's syndrome is an autoimmune condition characterized by glomerulonephritis and hemoptysis. The clinical presentation is correlated to the presence of anti glomerular basement membrane (anti-GBM). Pulmonary hemorrhage is closely correlated to smoking regardless of absolute anti-GBM titers [94]. It is presumed that the mechanical damage precipitated by cigarette smoke results in pulmonary antigen exposure that can both induce the production of antibodies and facilitate binding of those already circulating.

10. Smoking and other autoimmune diseases Smoking has been demonstrated to accelerate the progression of primary biliary cirrhosis (PBC) and to be a risk factor for the development of the disease, with past smoking associated with an OR of 1.6 [95]. These results have not been replicated due to the relative rareness of PBC; the precise mechanism is not yet apparent. Systemic sclerosis (SS) is a disorder characterized mainly by skin thickening, vasculitis, and immune dysfunction. No studies have associated smoking with increased prevalence of the disease, but several associations with disease manifestations have been noted. A study published in 2002 found that smokers were 3e4 times more prone to require treatment for digital ischemia [96]. That effect is considered to be related to the vascular effects of smoking, rather than to disease activity. Smoking has been associated with a 40e80% increase in the prevalence of multiple sclerosis (MS) [97]. Cigarette smoking has been associated with a 3-fold higher risk of transforming or hastening the transformation of relapsing-remitting forms of the disease into progressive forms [98]. Some epidemiologic studies described an association between smoking and chronic widespread pain (CWP) and pain at certain body sites like the back, neck, shoulders, and legs [99]. Furthermore, it was reported that patients with fibromyalgia who smoke reported significantly more pain, numbness, disease severity, and functional difficulties than non-smokers [100]. Fatigue and tender point count do not differ between smoker and nonsmoker fibromyalgia patients.

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11. Conclusion Smoking has multiple deleterious effects on the immune system causing relative immune deficiency, higher rates of infection and hazardous effects on various phases of many autoimmune diseases. Smoking plays a direct pathogenic role in the disease development of many conditions. Given the high costs of modern therapies, smoking prevention and cessation seem to be more essential than ever.

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