Peter Laszlo Lakatos, Tamas Szamosi, 1st Department of Medicine, Semmelweis University, Budapest, Hungary
Laszlo Lakatos, 1st Department of Medicine, Csolnoky F. County Hospital, Veszprem, Hungary
Correspondence to: Peter Laszlo Lakatos, MD, PhD, 1st Department of Medicine, Semmelweis University, Koranyi str. 2/A, H-1083, Hungary. email@example.com
Telephone: +36-1-2100278-1500 Fax: +36-1-3130250
Received: August 27, 2007 Revised: September 20, 2007
Smoking is an important environmental factor in inflammatory bowel disease (IBD), having different effects in ulcerative colitis (UC) and Crohn’s disease (CD). A recent meta-analysis partially confirmed previous findings that smoking was found to be protective against ulcerative colitis and, after onset of the disease, might improve its course, decreasing the need for colectomy. However, smoking increases the risk of developing Crohn’s disease and worsens its course, increasing the need for steroids, immunosuppressants and re-operations. Smoking cessation aggravates ulcerative colitis and improves Crohn’s disease. Data are however, largely conflictive as well as the potential mechanisms involved in this dual relationship are still unknown. In this review article, the authors review the role of smoking in inflammatory bowel diseases.
© 2007 WJG. All rights reserved.
Key words: Smoking; Crohn's disease; Ulcerative colitis; Phenotype
Lakatos PL, Szamosi T, Lakatos L. Smoking in inflammatory bowel diseases: Good, bad or ugly? World J Gastroenterol 2007; 13(46): 6134-6139
The pathogenesis of ulcerative colitis (UC) and Crohn’s disease (CD) has only been partly understood. Inflammatory bowel disease (IBD) is a multifactorial disease with probable genetic heterogeneity[1,2]. In addition, several environmental (eg, diet, smoking, measles or appendectomy) risk factors may contribute to its pathogenesis.
During the past decades, the incidence pattern of both diseases has changed significantly, showing some common but also quite distinct characteristics for the two disorders. Differences in geographic distribution, and particularly changes in incidence over time within one area, may provide insight into possible etiological factors. It is very unlikely however, that these rapid changes attributed to variations in the genetic factors. On the contrary, environmental factors are likely to play an important role. Diet, as a luminal antigen, was thought to be an important factor in the pathogenesis of IBD[1,5]. In the last two decades, there has been a shift in the lifestyle in Eastern Europe, Asia, and Central America, as the lifestyle, including the diet, became more “Westernized”. This possibility is further supported by the differences in incidence and prevalence found within one region.
A further important environmental factor studied extensively in both diseases is smoking. The link between smoking and (IBD) was first made in 1982 when Harries et al noticed a low proportion of ulcerative colitis patients were smokers. Two years later a case-control study by Somerville et al reported that the relative risk of developing Crohn’s disease was 4.8 in those who smoked before disease onset, and 3.5 for those with a current smoking habit. In recent years, IBD has been classified into subtypes/phenotypes that are distinct and based on age at onset, disease location, and clinical behaviour. Knowledge of this heterogeneity has led to the re-examination of genetic and environmental influences on IBD. The relationship between smoking and IBD however, is far more complex than previously realized as clinical subtypes have become apparent. In this article, the authors give an updated review on the role of smoking in IBD.
EFFECT OF SMOKING CESSASION AND SMOKING ON THE RISK OF DEVELOPING IBD
Risk for developing ulcerative colitis
Ulcerative colitis affects predominantly non-smokers and former smokers. The percentage of current smokers (smoking more than seven cigarettes per week) in a group of patients with UC is about 10%-15%[8,9]. These percentages are significantly lower than those observed in a control population matched for sex and age (25%-40%). The meta-analysis by Calkins, conducted more than 15 years ago, yielded a pooled odds ratio of 0.41 (0.34-0.48) for current smokers compared with lifetime non-smokers. The effect of smoking seems to only postpone the event, as the relative risk of UC was also higher in former smokers (OR: 1.64; 95% CI: 1.36-1.98). In a recent meta-analysis by Mahid et al comparable values were reported, which also included new available data. Current smoking decreased the risk for UC (OR: 0.58; 95% CI: 0.45-0.75), while former smoking was associated with an increased risk (OR: 1.79; 95% CI: 1.37-2.34). Interestingly, in patients who stopped smoking, UC developed in 52% of patients, in the first three years after cessation, as reported by Motley et al in concordance with other studies. In contrast, active smoking in early childhood was associated with a gradually increased risk for developing UC (OR for smoking start < 10 years: 7.02 and < 15 years: 3.46). The same trend was observed for passive smoking by the mother (OR: 1.53, 95% CI: 0.93-2.49).
The relationship between smoking and ulcerative colitis has also been examined at a population level. The prevalence of UC was five-fold increased in patients from the Mormon Church in Britain and Ireland, where smoking is strongly discouraged, compared with that of the general population. In contrast, CD was equally as common. In addition, a review of 56 epidemiological studies in Sweden over the time period from 1930 to 1990 demonstrated that the sex distribution of UC had changed from an earlier female predominance to a later male predominance. Over the same period, the proportions of smokers and ex-smokers among men and women have undergone reciprocal changes with an increase in women smokers relative to men, while the same change in predominance was not observed in contemporary pediatric studies. Somewhat contradictory, in a recent population-based case-control study, among others, ever smoking was also associated with increased risk (1.66; 95% CI: 1.17-2.35).
There are only very few data regarding the effect of smoking in indeterminate colitis[8,18]. The effect seems to be similar to that observed in UC, that is, a protective effect against the development of colitis and a possible beneficial effect on disease course.
Risk for developing Crohn’s disease
The percentage of current smokers in a group of patients with CD is significantly higher than that observed in a control population matched for sex and age (45%-55% vs 30%-40%). In concordance, an increased life-time risk was reported in current smokers when compared with non-smokers by both Calkins et al (OR: 2.0; 95% CI: 1.65-2.47) and in the more recent meta-analysis by Mahid et al (OR: 1.76; 95% CI: 1.40-2.22).
compared with never-smokers, former smokers were reported to have an increased risk of developing CD. This risk decreased only after four years of having quit smoking. In a recent population-based study by Bernstein et al, similar data were reported, both current smoking (OR: 1.96) and ever smoking (OR: 1.78) were associated with increased risk to develop CD. However, this later association could not be replicated in the recent meta-analysis by Mahid et al although a trend was observed (P = 0.08). In contrast, ever smoking was associated with increased risk (OR: 1.61; 95% CI: 1.27-2.03). The effect of passive smoking remains controversial. In one recent prospective study CD patients were more likely than controls to have prenatal smoke exposure (OR: 1.72; 95% CI: 1.1-2.71). In addition, the passive smoke exposure during childhood, with parents or other household members being smokers (OR: 2.04; 95% CI: 1.28-3.31) was also associated with increased risk, in concordance with previous data by Lashner et al.
EFFECT OF SMOKING AND ITS CESSATION ON DISEASE PHENOTYPE AND COURSE
Effect of smoking and its cessation on clinical course and extent of ulcerative colitis
Although the extent at diagnosis is not affected by smoking, UC usually runs a more benign disease course in smokers compared with non-smokers. Flare-up, hospitalization rates, the need for oral steroids and colectomy rates[22,23], are reported to be lower, while age at onset is older in smokers compared with non-smokers, though not in all studies. Relapse rates are lower in patients who began smoking after the diagnosis of UC. In concordance, in a recent Europe-wide population-based cohort the relapse rate was lower (Hazard Ratio: 0.8; 95% CI: 0.6-0.9) in smokers compared with non-smokers, while it was higher in women. In a retrospective analysis of a large series of patients with UC, current smoking was found to decrease the 10-year cumulative colectomy risk from 0.42 to 0.32. In concordance, a meta-analysis of several large series with a total of 1489 UC patients also found the risk for colectomy to be lower (OR: 0.57; 95% CI: 0.38-0.85) in current smokers compared with non-smokers.
In addition, in smokers with distal UC at diagnosis, the proximal extension of the disease is less frequent[22,27], while primary sclerosing cholangitis is observed almost exclusively in non-smokers. Disease regression was also more likely to occur in smokers compared with non-smokers or ex-smokers 5 years (30% vs 5% vs 8%), but not 10 years after the diagnosis. Also, those with extensive disease were the lightest smokers, whereas those with healthy colons were the heaviest smokers. Finally, current smokers have a lower incidence of pouchitis following coloproctectomy with ileal reservoir when compared with non-smokers[30,31].
In contrast, intriguing new data by Aldhous et al showed that current and non-smokers had an almost identical age at onset (31.1 vs 29.4 years) and this was delayed only in ex-smokers (46.5 years). Colectomy rates were not different. This group however, had a greater exposure to smoking compared with the group of current smokers.
A link between smoking habits and the course of UC has also been reported. In intermittent smokers, many patients note symptom exacerbation when they stop smoking, followed by symptom relief when they smoke again. In contrast, almost half of the intermittent smokers thought that their colitis symptoms improved while smoking at least 20 cigarettes per day. Moreover, smokers with UC who quit, experience an increase in disease activity, hospital admissions, and the need for major medical therapy (oral steroids, immunosuppressants), within the first years following the cessation of smoking. However, the risk of colectomy in the short-term was not increased compared with matched non-smokers and continuing smokers.
Effect of smoking and its cessation on disease location, behaviour, and disease progression in Crohn’s disease
Smoking is associated with disease location: most, but not all, studies report a higher prevalence of ileal disease and a lower prevalence of colonic involvement in smokers[34-36].
A recent review and previous data have demonstrated that smoking, when measured up to the time point of disease behavior classification, was associated more frequently with complicated disease, penetrating intestinal complications[34,37,38], and greater likelihood to progress to complicated disease, as defined by development of strictures or fistulae, and a higher relapse rate[2,39]. Of note, previous severity of the disease, as assessed from the therapeutics needs, was found to be similar in young patients who started smoking and in their matched controls. The need for steroids and immunosuppressants is increased in smokers compared with non-smokers. Whether the daily dose (eg, more than 15 cigarettes per day) or the total pack years smoked is more important in the abovementioned associations remains questionable.
The risk of surgery as well as the risk for further resections during disease course is also higher in smokers, in most studies[34,41,42]. These findings were reinforced by Cottone et al who have shown that macroscopic lesions on the ileal site of the anastomosis were observed 1 year after surgery in 70% of smokers, versus 35% of non-smokers and 27% of ex-smokers. The risk of symptomatic postoperative recurrence was more marked in heavy smokers than in mild smokers. Noteworthy, immunosuppressive therapy was found to neutralize the effect of smoking on the need for surgery.
However, the harmful effect of smoking on the course of CD is not a universal finding. Studies in patients from Israel and Hungary have not found differences in the need for surgery or for immunosuppressants between smokers and non-smokers[2,44,45], and patients with only colonic involvement are less sensitive to the harmful effects of smoking. Finally, the development and severity of perineal complications do not seem to be influenced by the smoking status.
In a recent paper by Aldhous et al using the Montreal classification, the harmful effect of smoking was only partially confirmed. Although current smoking was associated with less colonic disease, the smoking habits at diagnosis were not associated with time to development of stricturing disease, internal penetrating disease, perianal penetrating disease, or time to first surgery. Age at diagnosis was also similar in current smokers and non-smokers (28.3 years and 28.9 years) and was only delayed in ex-smokers (43.2 years). However, the way in which they measured tobacco exposure was different from previous studies. “Current smokers” were defined as those who were smoking at the time of diagnosis or event (penetrating or stricturing complication) and “ex-smokers” had stopped for at least one year before the diagnosis or event (eg, a patient could have continued smoking up to 1 year before developing a complication but was considered an “ex-smoker”).
The rationale for this may be that after surgery, the risk of endoscopic and clinical recurrence in former smokers who have not smoked for at least 1 year is similar to that of non-smokers. Similarly, CD activity in ex-smokers is not different from that of non-smokers, and is less marked than in current smokers. The beneficial effect of quitting smoking might be seen within the year following cessation. A large prospective intervention study by Cosnes et al performed in a selected group of 59 patients who stopped smoking following a smoking cessation intervention, examined the disease course from 1 year following smoking cessation onwards. The flare-up rate, therapeutic needs, and disease severity were similar in patients who had never smoked and in those who stopped smoking, and both had a better course than current smokers. Quitters had a 65% lower risk of flare-up compared with continuing smokers. The need for corticosteroids, immunosuppressive therapy, or a dose increase of immunosuppressants was also lower. Interestingly, after quitting, some patients developed UC-like lesions of the distal colon, whereas previously they had typical CD.
Finally, in a prospective study during pregnancy, the improvement of disease activity was observed only in smokers, in parallel with a decrease in the daily cigarette smoking.
The role of gender, familial disease, and ethnicity
The effect of smoking is to some extent different between male and female patients. In CD, women are affected more drastically by smoking. The relative risk associated with smoking for women may be greater than for men: one study demonstrated a three-fold difference.
This was already demonstrated by Sutherland et al in 1990, who reported that in a group of 174 patients who required surgery for Crohn’s disease, smokers had a 29% greater risk than non-smokers, over 10 years. However, the increased risk was more marked in females than males (OR: 4.2; 95% CI 2.0-4.2 in females and 1.5; 95% CI 0.8-0.6 in males). In Crohn’s colitis, smoking is clearly harmful for women, whereas colitis in men is not affected by smoking. In the study by Cosnes et al current smoking hastened disease onset (from 35 to 29 years of age) and increased the need for immunosuppressants, only in women.
In UC, current and ex-smoking delayed disease onset in men (from 25 to 42 years of age), but not in women. Similarly, when compared with non-smokers, male UC patients who smoked ran a more benign disease course as assessed by the decreased need for immunosuppressive therapy (8% vs 26%), whereas this difference was not observed in females as reported by Cosnes et al and again smoking delayed the onset of disease, only in males.
Thus, the effect of smoking in both UC and CD seems to be modulated by gender, with women being affected more disadvantageously than men. This phenomenon deserves even more attention, since smoking habits are changing in the Western population, with a trend to a greater prevalence of smokers among young women. A gender difference in smoking habits may be a possible explanation, since women use more filtered cigarettes and lighter cigarettes, and might consequently have a higher relative exposure to smoke than to nicotine. In addition, the negative effect of estrogens on proinflammatory cytokine gene regulation and lymphocyte interactions might also play an important role.
In Israel, no association was reported between smoking and CD in Jewish patients, although the opposite association was found for UC. Similarly, smoking was not associated to the risk for CD in some studies from Asia. The reason why CD in Israeli Jews or Koreans is not as sensitive to smoking as in other populations is not clear. Explanations might include differences in genetic and/or environmental factors (eg, type of tobacco, way of smoking or other alimentary factors).
A further interesting question is whether the effect of smoking is similar in familial versus sporadic cases. Family studies have reported a high concordance rate within families, between smoking habits and the phenotype of IBD, CD developing in smokers, and UC in non-smokers. The above association was refined in more recent studies. Tuvlin et al reported that ex-smokers made up an increasing percentage of older patients diagnosed with UC, accounting for more than 35% of the attributable risk of late onset (> 45 years) UC and a large component of the second peak in diagnosis. In contrast, current smoking accounted for a large percentage of patients diagnosed at a younger age with familial CD but not with sporadic CD (Table 1).
MECHANISMS BEHIND THE EFFECT OF SMOKING ON IBD
The reason behind the opposite effects of smoking observed in CD and UC remain obscure. The effects of smoking and nicotine are numerous and since the pathogenesis of inflammatory bowel disease is only partially understood, any discussion on the possible mechanisms can only be speculative. In addition, although nicotine is thought to be the most important agent responsible for the effect of smoking, one should be careful, as some effects usually associated with smoking may not follow the use of therapeutic nicotine formulations. Of note in most studies, side-effects (nausea, headache, dermatitis) of nicotine therapies were frequent and tended to be greater than the clinical benefit.
Smoking has numerous specific and non-specific effects. It has been shown to affect the immune system, by influencing cellular and humoral immunity. Nicotine has been shown to decrease the synthesis of proinflammatory molecules, for example, interleukin (IL)-1b and TNFa by mouse colonic mucosa as well as the production of mucosal eicosanoids and some proinflammatory cytokines by human mononuclear cells (eg, IL-2, IL-8, and TNFa) partly by its action on the nicotinic acetylcholine receptor a7 subunit. Further evidence for anti-inflammatory properties comes from a surgically-induced ileus model, where carbon monoxide-treated mice were shown to have three times higher levels of IL-10. Macrophages from smokers express a selective functional deficiency in their ability to kill intracellular bacteria. Finally, chronic exposure of rats to nicotine inhibits the antibody-forming cell response, impairs the antigen-mediated signaling in T-cells and induces T-cell anergy. Other effects of nicotine or smoking on the intestine include the alteration of gut motility, the reduction of smooth muscle tone and contractility (modulated by nitric oxide), decreased permeability, and alterations in the microcirculation, Furthermore, smoking also increases lipid peroxidation.
In UC, the colonic mucosal layer is thin or absent, in contrast to CD where it is significantly thicker, with nicotine having been shown to increase mucin synthesis[67,68]. 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. Beneficial effects of nicotine in active UC may be associated with a decrease in IL-8 expression. Hypoperfusion of the rectum and of acutely damaged colonic tissue may play an additional role. On the contrary, in CD, several plasma antioxidant parameters are altered, the total radical-trapping antioxidant potential is decreased, and abnormalities are present in the microvasculature. Smoking through increased carbon monoxide concentration might amplify the impairment in the vasodilation capacity of chronically inflamed microvessels, resulting in ischemia and perpetuating ulceration and fibrosis. Furthermore, smoking is known to increase the thrombotic potential associated with vascular damage. A defect in bacterial clearance or macrophage deficiency might also play an important role.
In conclusion, smoking plays a dual role in IBD by increasing the risk for CD and decreasing that of UC. In an individual who is genetically at risk for IBD, smoking might be an important factor in determining disease phenotype. In addition, smoking also affects the disease course. It improves UC and worsens CD, more markedly in women, while smoking cessation is followed rapidly by a reversed effect. Since smoking is associated with several additional deleterious effects (eg, cardiovascular, lung cancer risk), gastroenterologists should encourage both UC and CD patients to quit smoking. Before stopping, UC patients should be informed about the potential risk of increase in disease activity, without a higher risk for surgery. In CD, the benefit of smoking cessation is well-proven, since patients who continue to smoke have a more severe course of disease with more complications, while ex-smokers run a similar course of disease to non-smokers.
1 Lakatos PL, Fischer S, Lakatos L, Gal I, Papp J. Current concept on the pathogenesis of inflammatory bowel disease- crosstalk between genetic and microbial factors: pathogenic bacteria and altered bacterial sensing or changes in mucosal integrity take "toll" ? World J Gastroenterol 2006; 12: 1829-1841 PubMed
2 Lakatos PL, Szalay F, Tulassay Z, Molnar T, Kovacs A, Gasztonyi B, Papp J, Lakatos L. Clinical presentation of Crohn's disease. association between familial disease, smoking, disease phenotype, extraintestinal manifestations and need for surgery. Hepatogastroenterology 2005; 52: 817-822 PubMed
3 Lakatos PL. Recent trends in the epidemiology of inflammatory bowel diseases: up or down? World J Gastroenterol 2006; 12: 6102-6108 PubMed
4 Russel MG. Changes in the incidence of inflammatory bowel disease: what does it mean? Eur J Intern Med 2000; 11: 191-196 PubMed
5 Cashman KD, Shanahan F. Is nutrition an aetiological factor for inflammatory bowel disease? Eur J Gastroenterol Hepatol 2003; 15: 607-613 PubMed
6 Harries AD, Baird A, Rhodes J. Non-smoking: a feature of ulcerative colitis. Br Med J (Clin Res Ed) 1982; 284: 706
7 Somerville KW, Logan RF, Edmond M, Langman MJ. Smoking and Crohn's disease. Br Med J (Clin Res Ed) 1984; 289: 954-956 PubMed
8 Cosnes J, Nion-Larmurier I, Afchain P, Beaugerie L, Gendre JP. Gender differences in the response of colitis to smoking. Clin Gastroenterol Hepatol 2004; 2: 41-48 PubMed
9 Srivasta ED, Newcombe RG, Rhodes J, Avramidis P, Mayberry JF. Smoking and ulcerative colitis: a community study. Int J Colorectal Dis 1993; 8: 71-74 PubMed
10 Calkins BM. A meta-analysis of the role of smoking in inflammatory bowel disease. Dig Dis Sci 1989; 34: 1841-1854
11 Mahid SS, Minor KS, Soto RE, Hornung CA, Galandiuk S. Smoking and inflammatory bowel disease: a meta-analysis. Mayo Clin Proc 2006; 81: 1462-1471 PubMed
12 Motley RJ, Rhodes J, Ford GA, Wilkinson SP, Chesner IM, Asquith P, Hellier MD, Mayberry JF. Time relationships between cessation of smoking and onset of ulcerative colitis. Digestion 1987; 37: 125-127 PubMed
13 Boyko EJ, Koepsell TD, Perera DR, Inui TS. Risk of ulcerative colitis among former and current cigarette smokers. N Engl J Med 1987; 316: 707-710 PubMed
14 Mahid SS, Minor KS, Stromberg AJ, Galandiuk S. Active and passive smoking in childhood is related to the development of inflammatory bowel disease. Inflamm Bowel Dis 2007; 13: 431-438 PubMed
15 Penny WJ, Penny E, Mayberry JF, Rhodes J. Prevalence of inflammatory bowel disease amongst Mormons in Britain and Ireland. Soc Sci Med 1985; 21: 287-290 PubMed
16 Tysk C, Jarnerot G. Has smoking changed the epidemiology of ulcerative colitis? Scand J Gastroenterol 1992; 27: 508-512 PubMed
17 Bernstein CN, Rawsthorne P, Cheang M, Blanchard JF. A population-based case control study of potential risk factors for IBD. Am J Gastroenterol 2006; 101: 993-1002 PubMed
18 Meucci G, Bortoli A, Riccioli FA, Girelli CM, Radaelli F, Rivolta R, Tatarella M. Frequency and clinical evolution of indeterminate colitis: a retrospective multi-centre study in northern Italy. GSMII (Gruppo di Studio per le Malattie Infiammatorie Intestinali). Eur J Gastroenterol Hepatol 1999; 11: 909-913 PubMed
19 Lakatos L, Mester G, Erdelyi Z, Balogh M, Szipocs I, Kamaras G, Lakatos PL. Striking elevation in incidence and prevalence of inflammatory bowel disease in a province of western Hungary between 1977-2001. World J Gastroenterol 2004; 10: 404-409 PubMed
20 Persson PG, Ahlbom A, Hellers G. Inflammatory bowel disease and tobacco smoke--a case-control study. Gut 1990; 31: 1377-1381 PubMed
21 Lashner BA, Shaheen NJ, Hanauer SB, Kirschner BS. Passive smoking is associated with an increased risk of developing inflammatory bowel disease in children. Am J Gastroenterol 1993; 88: 356-359 PubMed
22 Mokbel M, Carbonnel F, Beaugerie L, Gendre JP, Cosnes J. Effect of smoking on the long-term course of ulcerative colitis. Gastroenterol Clin Biol 1998; 22: 858-862 PubMed
23 Boyko EJ, Perera DR, Koepsell TD, Keane EM, Inui TS. Effects of cigarette smoking on the clinical course of ulcerative colitis. Scand J Gastroenterol 1988; 23: 1147-1152 PubMed
24 Fraga XF, Vergara M, Medina C, Casellas F, Bermejo B, Malagelada JR. Effects of smoking on the presentation and clinical course of inflammatory bowel disease. Eur J Gastroenterol Hepatol 1997; 9: 683-687 PubMed
25 Hoie O, Wolters F, Riis L, Aamodt G, Solberg C, Bernklev T, Odes S, Mouzas IA, Beltrami M, Langholz E, Stockbrugger R, Vatn M, Moum B. Ulcerative colitis: patient characteristics may predict 10-yr disease recurrence in a European-wide population-based cohort. Am J Gastroenterol 2007; 102: 1692-1701 PubMed
26 Cosnes J. Tobacco and IBD: relevance in the understanding of disease mechanisms and clinical practice. Best Pract Res Clin Gastroenterol 2004; 18: 481-496 PubMed
27 Samuelsson SM, Ekbom A, Zack M, Helmick CG, Adami HO. Risk factors for extensive ulcerative colitis and ulcerative proctitis: a population based case-control study. Gut 1991; 32: 1526-1530 PubMed
28 Loftus EV Jr, Sandborn WJ, Tremaine WJ, Mahoney DW, Zinsmeister AR, Offord KP, Melton LJ 3rd. Primary sclerosing cholangitis is associated with nonsmoking: a case-control study. Gastroenterology 1996; 110: 1496-1502
29 Aldhous MC, Drummond HE, Anderson N, Baneshi MR, Smith LA, Arnott ID, Satsangi J. Smoking habit and load influence age at diagnosis and disease extent in ulcerative colitis. Am J Gastroenterol 2007; 102: 589-597 PubMed
30 Merrett MN, Mortensen N, Kettlewell M, Jewell DO. Smoking may prevent pouchitis in patients with restorative proctocolectomy for ulcerative colitis. Gut 1996; 38: 362-364 PubMed
31 Stahlberg D, Gullberg K, Liljeqvist L, Hellers G, Lofberg R. Pouchitis following pelvic pouch operation for ulcerative colitis. Incidence, cumulative risk, and risk factors. Dis Colon Rectum 1996; 39: 1012-1018 PubMed
32 Rudra T, Motley R, Rhodes J. Does smoking improve colitis? Scand J Gastroenterol Suppl 1989; 170: 61-63; discussion 66-68 PubMed
33 Beaugerie L, Massot N, Carbonnel F, Cattan S, Gendre JP, Cosnes J. Impact of cessation of smoking on the course of ulcerative colitis. Am J Gastroenterol 2001; 96: 2113-2116 PubMed
34 Lindberg E, Jarnerot G, Huitfeldt B. Smoking in Crohn's disease: effect on localisation and clinical course. Gut 1992; 33: 779-782 PubMed
35 Russel MG, Volovics A, Schoon EJ, van Wijlick EH, Logan RF, Shivananda S, Stockbrugger RW. Inflammatory bowel disease: is there any relation between smoking status and disease presentation? European Collaborative IBD Study Group. Inflamm Bowel Dis 1998; 4: 182-186 PubMed
36 Mahid SS, Minor KS, Stevens PL, Galandiuk S. The Role of Smoking in Crohn's Disease as Defined by Clinical Variables. Dig Dis Sci 2007; 52: 2897-903 PubMed
37 Picco MF, Bayless TM. Tobacco consumption and disease duration are associated with fistulizing and stricturing behaviors in the first 8 years of Crohn's disease. Am J Gastroenterol 2003; 98: 363-368 PubMed
38 Louis E, Michel V, Hugot JP, Reenaers C, Fontaine F, Delforge M, El Yafi F, Colombel JF, Belaiche J. Early development of stricturing or penetrating pattern in Crohn's disease is influenced by disease location, number of flares, and smoking but not by NOD2/CARD15 genotype. Gut 2003; 52: 552-557 PubMed
39 Cosnes J, Carbonnel F, Carrat F, Beaugerie L, Cattan S, Gendre J. Effects of current and former cigarette smoking on the clinical course of Crohn's disease. Aliment Pharmacol Ther 1999; 13: 1403-1411 PubMed
40 Cosnes J, Carbonnel F, Beaugerie L, Le Quintrec Y, Gendre JP. Effects of cigarette smoking on the long-term course of Crohn's disease. Gastroenterology 1996; 110: 424-431 PubMed
41 Breuer-Katschinski BD, Hollander N, Goebell H. Effect of cigarette smoking on the course of Crohn's disease. Eur J Gastroenterol Hepatol 1996; 8: 225-228 PubMed
42 Sutherland LR, Ramcharan S, Bryant H, Fick G. Effect of cigarette smoking on recurrence of Crohn's disease. Gastroenterology 1990; 98: 1123-1128 PubMed
43 Cottone M, Rosselli M, Orlando A, Oliva L, Puleo A, Cappello M, Traina M, Tonelli F, Pagliaro L. Smoking habits and recurrence in Crohn's disease. Gastroenterology 1994; 106: 643-648 PubMed
44 Odes HS, Fich A, Reif S, Halak A, Lavy A, Keter D, Eliakim R, Paz J, Broide E, Niv Y, Ron Y, Villa Y, Arber N, Gilat T. Effects of current cigarette smoking on clinical course of Crohn's disease and ulcerative colitis. Dig Dis Sci 2001; 46: 1717-1721 PubMed
45 Fidder HH, Avidan B, Lahav M, Bar-Meir S, Chowers Y. Clinical and demographic characterization of Jewish Crohn's disease patients in Israel. J Clin Gastroenterol 2003; 36: 8-12 PubMed
46 Aldhous MC, Drummond HE, Anderson N, Smith LA, Arnott ID, Satsangi J. Does cigarette smoking influence the phenotype of Crohn's disease? Analysis using the Montreal classification. Am J Gastroenterol 2007; 102: 577-588
47 Cosnes J, Beaugerie L, Carbonnel F, Gendre JP. Smoking cessation and the course of Crohn's disease: an intervention study. Gastroenterology 2001; 120: 1093-1099 PubMed
48 Agret F, Cosnes J, Hassani Z, Gornet JM, Gendre JP, Lemann M, Beaugerie L. Impact of pregnancy on the clinical activity of Crohn's disease. Aliment Pharmacol Ther 2005; 21: 509-513 PubMed
49 Motley RJ, Rhodes J, Kay S, Morris TJ. Late presentation of ulcerative colitis in ex-smokers. Int J Colorectal Dis 1988; 3: 171-175 PubMed
50 Jha P, Ranson MK, Nguyen SN, Yach D. Estimates of global and regional smoking prevalence in 1995, by age and sex. Am J Public Health 2002; 92: 1002-1006 PubMed
51 Zeman MV, Hiraki L, Sellers EM. Gender differences in tobacco smoking: higher relative exposure to smoke than nicotine in women. J Womens Health Gend Based Med 2002; 11: 147-153 PubMed
52 Rider V, Abdou NI. Gender differences in autoimmunity: molecular basis for estrogen effects in systemic lupus erythematosus. Int Immunopharmacol 2001; 1: 1009-1024 PubMed
53 Reif S, Lavy A, Keter D, Fich A, Eliakim R, Halak A, Broide E, Niv Y, Ron Y, Patz J, Odes S, Villa Y, Gilat T. Lack of association between smoking and Crohn's disease but the usual association with ulcerative colitis in Jewish patients in Israel: a multicenter study. Am J Gastroenterol 2000; 95: 474-478 PubMed
54 Jang JY, Kim HJ, Jung JH, Chae MJ, Kim NH, Lee SK, Joo KR, Dong SH, Kim BH, Chang YW, Lee JI, Chang R. The role of smoking as a risk factor in inflammatory bowel diseases: single center study in Korea. Korean J Gastroenterol 2006; 47: 198-204 PubMed
55 Halfvarson J, Jess T, Magnuson A, Montgomery SM, Orholm M, Tysk C, Binder V, Jarnerot G. Environmental factors in inflammatory bowel disease: a co-twin control study of a Swedish-Danish twin population. Inflamm Bowel Dis 2006; 12: 925-933 PubMed
56 Tuvlin JA, Raza SS, Bracamonte S, Julian C, Hanauer SB, Nicolae DL, King AC, Cho JH. Smoking and inflammatory bowel disease: trends in familial and sporadic cohorts. Inflamm Bowel Dis 2007; 13: 573-579 PubMed
57 Pullan RD, Rhodes J, Ganesh S, Mani V, Morris JS, Williams GT, Newcombe RG, Russell MA, Feyerabend C, Thomas GA. Transdermal nicotine for active ulcerative colitis. N Engl J Med 1994; 330: 811-815 PubMed
58 Motley RJ, Rhodes J, Williams G, Tavares IA, Bennett A. Smoking, eicosanoids and ulcerative colitis. J Pharm Pharmacol 1990; 42: 288-289 PubMed
59 van Dijk AP, Meijssen MA, Brouwer AJ, Hop WC, van Bergeijk JD, Feyerabend C, Wilson JH, Zijlstra FJ. Transdermal nicotine inhibits interleukin 2 synthesis by mononuclear cells derived from healthy volunteers. Eur J Clin Invest 1998; 28: 664-671 PubMed
60 Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, Wang H, Yang H, Ulloa L, Al-Abed Y, Czura CJ, Tracey KJ. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 2003; 421: 384-388 PubMed
61 King TE Jr, Savici D, Campbell PA. Phagocytosis and killing of Listeria monocytogenes by alveolar macrophages: smokers versus nonsmokers. J Infect Dis 1988; 158: 1309-1316 PubMed
62 Geng Y, Savage SM, Razani-Boroujerdi S, Sopori ML. Effects of nicotine on the immune response. II. Chronic nicotine treatment induces T cell anergy. J Immunol 1996; 156: 2384-2390 PubMed
63 Green JT, Richardson C, Marshall RW, Rhodes J, McKirdy HC, Thomas GA, Williams GT. Nitric oxide mediates a therapeutic effect of nicotine in ulcerative colitis. Aliment Pharmacol Ther 2000; 14: 1429-1434 PubMed
64 Suenaert P, Bulteel V, Den Hond E, Hiele M, Peeters M, Monsuur F, Ghoos Y, Rutgeerts P. The effects of smoking and indomethacin on small intestinal permeability. Aliment Pharmacol Ther 2000; 14: 819-822 PubMed
65 Danese S. Inflammation and the mucosal microcirculation in inflammatory bowel disease: the ebb and flow. Curr Opin Gastroenterol 2007; 23: 384-389 PubMed
66 Pullan RD. Colonic mucus, smoking and ulcerative colitis. Ann R Coll Surg Engl 1996; 78: 85-91 PubMed
67 Finnie IA, Campbell BJ, Taylor BA, Milton JD, Sadek SK, Yu LG, Rhodes JM. Stimulation of colonic mucin synthesis by corticosteroids and nicotine. Clin Sci (Lond) 1996; 91: 359-364 PubMed
68 Zijlstra FJ, Srivastava ED, Rhodes M, van Dijk AP, Fogg F, Samson HJ, Copeman M, Russell MA, Feyerabend C, Williams GT. Effect of nicotine on rectal mucus and mucosal eicosanoids. Gut 1994; 35: 247-251 PubMed
69 Sher ME, Bank S, Greenberg R, Sardinha TC, Weissman S, Bailey B, Gilliland R, Wexner SD. The influence of cigarette smoking on cytokine levels in patients with inflammatory bowel disease. Inflamm Bowel Dis 1999; 5: 73-78
70 Hatoum OA, Binion DG, Otterson MF, Gutterman DD. Acquired microvascular dysfunction in inflammatory bowel disease: Loss of nitric oxide-mediated vasodilation. Gastroenterology 2003; 125: 58-69 PubMed
71 Genser D, Kang MH, Vogelsang H, Elmadfa I. Status of lipidsoluble antioxidants and TRAP in patients with Crohn's disease and healthy controls. Eur J Clin Nutr 1999; 53: 675-679 PubMed
S- Editor Liu Y L- Editor Alpini GD E- Editor Liu Y