Tobacco and IBD: relevance in the understanding of disease mechanisms and clinical practice

Best Practice & Research Clinical Gastroenterology Vol. 18, No. 3, pp. 481–496, 2004 doi:10.1016/j.bpg.2003.12.003 available online at http://www.sciencedirect.com

3 Tobacco and IBD: relevance in the understanding of disease mechanisms and clinical practice Jacques Cosnes* Service de Gastroente´rologie et Nutrition, Hoˆpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75571 Paris cedex 12, France

Current smoking protects against ulcerative colitis and, after onset of the disease, improves 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 reoperations. Smoking cessation aggravates ulcerative colitis and improves Crohn’s disease. The effects of smoking are the sum of contradictory effects of various substances, including nicotine and carbon monoxide, and are modulated by gender, genetic background, disease location and activity, cigarette dose and nicotine concentration. Smokers with ulcerative colitis should not be discouraged from stopping smoking but encouraged to stop, to reduce their risk of cardiopulmonary tobacco-related diseases. In Crohn’s disease, smoking cessation has become a major therapeutic goal, particularly in young women and in patients with ileal involvement. A large amount of supportive information, use of nicotine-replacement therapies and antidepressants, and individual counselling might aid the patient in quitting. Key words: addiction; Crohn’s disease; inflammatory bowel disease; nicotine; smoking; tobacco; ulcerative colitis.

The development of inflammatory bowel disease (IBD) is the result of an interaction between a predisposing genetic background and various yet unidentified environmental factors. At the present time, among many putative factors only two have been shown to play a significant role—cigarette smoking and appendicectomy. The role of appendicectomy is limited to a protective effect against the development of ulcerative colitis (UC)1 and a beneficial effect on the course of the disease, provided the appendectomy was performed before disease onset.2 In Crohn’s disease (CD), it is not clear that appendicectomy has any effect. The role of smoking has been studied extensively in both diseases and appears to be crucial.

* Tel.: þ 1-49-28-31-68; Fax: þ 1-49-28-31-88. E-mail address: [email protected]. 1521-6918/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved.

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EFFECT OF CURRENT SMOKING ON INFLAMMATORY BOWEL DISEASES Risk of developing ulcerative colitis Ulcerative colitis affects predominantly non-smokers and former smokers.3 The percentage of current smokers (smoking more than seven cigarettes per week) in a group of patients with UC is about 10 – 15%.4 – 6 These percentages are significantly lower than those observed in a control population matched for sex and age (25 – 40%). The meta-analysis by Calkins3 yielded a pooled odds ratio of 0.41 (0.34 –0.48) for current smokers compared with lifetime non-smokers. The effect of smoking is only suspending, as the relative risk of UC is not decreased in former smokers. Course of ulcerative colitis Ulcerative colitis runs a more benign disease course in smokers than in non-smokers: flare-up and hospitalization rates7, the need for oral steroids5 and, more importantly, colectomy rate, are lower in smokers than non-smokers. 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 0.32.5 A meta-analysis of several large series of UC totalling 1489 patients5,7 – 11 gives an odds ratio of 0.57 (95% confidence intervals 0.38 – 0.85) for total colectomy in current smokers compared to non-smokers (Figure 1). In patients with distal UC at diagnosis, retrograde extension of the disease process is less frequent in smokers than in non-smokers5,12, and smoking could be a factor associated with a decreased risk of colonic carcinoma associated with UC.13 Primary sclerosing cholangitis is observed almost exclusively in non-smokers.14 Finally, current smokers have a lower incidence of pouchitis following coloproctectomy with ileal reservoir when compared to non-smokers.15,16 Indeterminate colitis They are few data regarding the effect of smoking in indeterminate colitis.4,17 The effect seems very similar to that observed in UC, i.e. a protective effect against the development of colitis and a beneficial effect on disease course.4,17 Holdstock 1984 Boyko 1988 Fraga 1997 Woseth 1998 Mokbel 1998 Odes 2001

>

Summary odds ratio

0

Smoking beneficial

1

10

Smoking deleterious

Figure 1. Individual and summary odds ratios and 95% confidence intervals for current smokers compared with non-smokers for colectomy in ulcerative colitis patients.

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Risk of 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 versus 30 – 40%). The meta-analysis by Calkins3 yielded a pooled odds ratio of 2.0 (1.65 –2.47) in current smokers when compared to life-time non-smokers. Smoking might determine disease location: most studies reporting a higher prevalence of ileal disease and a lower prevalence of colonic involvement in smokers.18,19 The effect of passive smoking remains controversial.20,21 Flare-ups of Crohn’s disease A cohort study demonstrated that current smoking increases by more than 50% the risk of flare-up compared to never-smokers.22 The effect of smoking was independent of gender, age, duration of disease and current therapy. It differed according to the location of the lesions—patients with active colonic lesions were less sensitive. The effect was dose dependent and significant from a daily dose of 15 cigarettes per day.22 This harmful effect of smoking is not strengthened by the concomitant use of oral contraceptives.23,24 Current smoking might also decrease the efficacy of treatment of flares, in particular the response rate to infliximab.25 Long-term evolution of Crohn’s disease Smoking is associated with more frequent penetrating intestinal complications9,18,26,27 and a lower quality of life.28 It is not because their disease is more severe that some patients with CD smoke. Indeed, the 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.29 The need for steroids and immunosuppressants is increased in smokers compared to non-smokers.19,29 This effect depends on the daily cigarette dose and not the cumulative consumption.29 The risk of being operated on at least once during disease course is also usually increased in smokers versus non-smokers.18,30 The deleterious effect of smoking in CD is particularly manifest in patients who have been operated on. In such patients, Cottone et al.31 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 cumulative rates of clinical and surgical recurrence, respectively, were found to be consistently more elevated in smokers than in non-smokers (Table 1).31 – 34 The risk of symptomatic postoperative recurrence was more marked in heavy smokers (smoking more than 15 cigarettes per day) than in mild smokers.31,34 Of note, immunosuppressive therapy was found to neutralize the effect of smoking on the need for surgery.29 The effect of smoking is large enough to justify a stratification on smoking habits in randomized trials assessing the efficacy of a therapeutic regimen to prevent recurrence. However, the harmful effect of smoking on the course of CD is not a universal finding. Studies in patients from Israel have not found differences in the need for operation or for immunosuppressants between smokers and non-smokers10,35, and patients with colonic involvement only are less sensitive to the harmful effect of smoking.4 Finally, development and severity of anoperineal disease seem not to be

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Table 1. Effect of smoking on the risk of postoperative recurrence after surgery in Crohn’s disease. Surgical recurrence (reoperation rate)

Clinical recurrence

No. Delay Non-smokers Smokers No. Delay Non-smokers Smokers Reference patients (years) (%) (%) patients (years) (%) (%) 32 31 30 33 88 a

163 92

6 3.5

40

73a

46

69a

174 163 161 92 210

10 6 10 3.5 10

41 8 33 20 30

70a 24a 64a 50a 52a

P , 0:01 compared to non-smokers.

influenced by smoking status.22 However, the healing rate after transanal flapadvancement is decreased in smokers when compared to non-smokers.36 THE EFFECTS OF SMOKING ON SUBGROUPS OF PATIENTS Sex-based differences The effect of smoking shows some differences between male and female patients. In CD, women are more affected by smoking. The study by Sutherland et al.32 first reported a doubled proportion of early postoperative recurrences in female smokers compared to female non-smokers, whereas there was no significant differences between male smokers and non-smokers. In Crohn’s colitis, smoking is clearly harmful in women, whereas colitis of men is not affected by smoking.4 In UC, Motley et al.37 noticed that current smoking delayed disease onset in men but not in women. Similarly, when compared to non-smokers, male UC patients who smoked ran a more benign disease course, whereas this difference was not observed in females.4 In other words, the effect of smoking in colitis-beneficial in UC and harmful in Crohn’s colitis—is modulated by gender, with women being at a greater disadvantage than men. Differences in the way the sexes smoke (women use more filter cigarettes and more light cigarettes, and have a higher relative exposure to smoke than to nicotine38) and the negative effect of estrogens on proinflammatory cytokine gene regulation and T– B cell interactions39 are possible explanations. Ethnicity In Israel, there is no association between smoking and CD in Jewish patients40, although the opposite association exists in UC. The reason why CD in Israeli Jews is not so sensitive to smoking as in other populations is not clear. Genetic factors are probably not involved because we have observed that, within a population of Jewish patients living in France, smokers-but not non-smokers-show an increased requirement for immunosuppressants, just as in non-Jewish patients (unpublished data). Other explanations might be environmental, relative to the kind of tobacco used, the way of smoking or some other confounding factor, notably alimentary factors.

Tobacco and IBD 485

Family studies Family studies have reported a high concordance rate inside a family between smoking habits and the phenotype of IBD, CD developing in smokers and UC in non-smokers.41 Bridger et al.42 have studied sibling pairs discordant for both smoking and IBD phenotype to investigate whether smoking determines the type of IBD that develops in individuals with very similar genetic susceptibility. Smoking at diagnosis was associated with the development of CD in all of the familial patients. Smokers were also protected from UC. Of 89 sibling pairs discordant for smoking at diagnosis, 23 were also discordant for disease type. In 21 of these, CD occurred in the smoker and UC in the non-smoker. Thus tobacco consumption acts on the IBD genetic predisposition to shift the phenotype from UC towards CD. Twins studies also confirmed the determining role of smoking habits upon the IBD phenotype, and their significance for discordance for disease.43

EFFECT OF SMOKING CESSATION Ulcerative colitis Stopping smoking increases the risk of developing UC when compared to neversmokers. This increased risk—about 1.64 (1.36– 1.98)3—persists during the 2 to 3 years following smoking cessation.37 A link between smoking habit and UC course in intermittent smokers has also been reported. Many patients note symptom exacerbation when they stop smoking, followed by symptom relief when they smoke again.37 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.44 However, the risk of colectomy in the short term is not increased compared to matched non-smokers and continuing smokers.44 Crohn’s disease Compared to never-smokers, former smokers have an increased risk of developing CD.3 This risk decreases only after 4 years of quitting.3 After surgery, the risk of endoscopic and clinical recurrence in former smokers who had quit at least 1 year before is similar to that of non-smokers.31 Similarly, CD activity in ex-smokers is no different to that of non-smokers, and less marked than in current smokers.22 The beneficial effect of stopping smoking might be seen within the year following cessation: a study in young women showed that the improvement of disease activity during pregnancy was observed only in smokers, in parallel with a decrease of the daily cigarette consumption.45 A prospective study performed in a selected group of 59 patients who stopped smoking following a smoking cessation intervention46 examined the disease course from 1 year after the quit date. Regarding the flare-up rate and therapeutic needs, disease severity was similar in patients who had never smoked and in those who stopped smoking, and both had a better course than continuing smokers. Quitters had a 65% decreased risk of flare-up compared with paired continuing smokers. They were less likely to require corticosteroids, start immunosuppressive therapy, or require an increased dose of immunosuppressants

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100 Continuing smokers Quitters Non-smokers

80 60 40 20

Su rg er y

or m od ifi ed

co ur se

st ar te d IS

St er oi d

Fl ar eup

0

Figure 2. Respective 36-month cumulative rates (%) of flare-up, steroid course, start or change of immunosuppressants (IS) and excisional surgery in Crohn’s disease patients who quit smoking (quitters) compared to matched controls, continuing smokers and non-smokers.

(Figure 2). Interestingly, after quitting, some patients developed UC-like lesions of the distal colon whereas they had typical CD before.

SMOKING AND THE DISEASE MECHANISMS The reasons why smoking has an opposite effect in CD and UC remain obscure. The understanding of this duality is complicated by the variability of the effects according to the populations studied, the absence of an appropriate animal model and the complexity of tobacco smoke, which contains hundreds of different substances including nicotine, free radicals and carbon monoxide. Putative mechanisms of the effect of smoking in IBD Non-specific effects of smoking Nicotine modifies the thickness of adherent mucus to the colonic mucosa in rabbits47 and abolishes the synthesis of IL-1b and TNFa by mouse colonic mucosa.48 In man, nicotine decreases the production of mucosal eicosanoids49 and some proinflammatory cytokines by human mononuclear cells, e.g. IL-250, TNFa51 and IL-8.52 Other pertinent effects of nicotine or tobacco smoke on the intestine are the reduction of smooth muscle tone and contractile activity as a result of the release of nitric oxide53, modified permeability to macromolecules54,55 and changes in the microcirculation and transient ischemia.55 Moreover, cigarette smoke increases lipid peroxidation56 and modifies the immune response. Macrophages from smokers express a selective functional deficiency in their ability to kill intracellular bacteria57 and carbon monoxide at low concentrations inhibits the lipopolysaccharide-induced expression of proinflammatory cytokines (TNFa, IL-1b and macrophage inflammatory protein-1b) and increases that

Tobacco and IBD 487

of IL-10.58 Finally, chronic exposure of rats to nicotine inhibits the antibody-forming cell response, impairs the antigen-mediated signalling in T cells and induces T-cell anergy.59 Smoking and animal models of colitis The effect of nicotine and tobacco smoke has been studied in different experimental models of colitis, with various results (Table 2). In these models, except in the IL-10 2=2 model, cigarette exposure or nicotine drinking were given before the completion of the experimental colitis and during a relative short period. The dose of nicotine was highly variable, from 2.5 to 250 mg/ml of drinking water, which, when given ad libitum, corresponds to daily nicotine consumptions equivalent to 3 to . 100 cigarettes per day. In general, cigarette smoke and nicotine had a beneficial effect on the colonic damage, but this effect was reversed at high dose. The effect of nicotine was abolished by the ganglion blocker hexamethonium. The same dose of nicotine that was beneficial in colitis worsened small-bowel lesions. Finally, whereas carbon monoxide aggravated ischemia, it was found to have potent anti-inflammatory effects on the macrophages of IL-10 2 /2 mice.60 Therefore the same substance-either nicotine or carbon monoxide-can exert opposite effects depending on dose, duration of exposure and the target being examined. Pathogenic effects of smoking in IBD Ulcerative colitis can occur if mucosal protection breaks down because of a defect in the mucus layer. In UC, the colonic mucus layer is significantly thinner or absent, whereas in CD it is significantly thicker.61 Nicotine increases mucin synthesis in UC patients.62 However, transdermal nicotine has no effect on mucin gene transcription.63 Smokers with IBD have a significant reduction in mucosal cytokine levels, specifically, IL-1b and IL8 for patients with UC and IL-8 for patients with CD.64 Beneficial effects of nicotine in active UC can result from a decrease of IL-8 expression.63 Of note in this setting is the fact that the beneficial effect of appendectomy, which suppresses an important site of activation of autoreactive T cells involved in colonic inflammation, appears additive to that of current smoking.2 Hypoperfusion of the rectum and of acutely damaged colonic tissue can play an additional role.65 Conversely, CD is characterized by a decreased total radical-trapping antioxidant potential66 and abnormalities of the microvasculature.67 Smoking through increased carbon monoxide concentration might amplify the impairment in vasodilation capacity in chronically inflamed microvessels, resulting in ischemia and perpetuating ulceration and fibrosis.65 A defect in bacterial clearance or macrophage deficiency might also have a detrimental role. Relevance to understand the mechanisms of IBD The sensitivity of IBD to smoking concerns both disease onset and disease course. Smoking (or smoking cessation) has a trigger role and, on the same predisposing genetic background, could be a major determinant of the disease phenotype: CD or UC. Smoking can also recruit patients who would not have had IBD if they had never smoked. Then, after disease onset, smoking (or smoking cessation) either protects the intestine or perpetuates the mucosal damage, according to many factors: † gender (women are more susceptible to the harmful effect than men) † disease location (the protective effect is more efficient in the distal intestine) † degree of inflammation (through decreased tissue perfusion, smoking aggravates chronic inflammatory state, although it might improve acute colitis)

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Table 2. Effect of smoking exposure and nicotine drinking in different models of colitis. Reference

Model

Agent

Main findings

89

DNBS colitis (rat)

Cigarette smoke

90

DNBS colitis (rat)

Cigarette smoke þhexamethonium

91

TNBS colitis (rat)

Cigarette smoke þ LTB4 antagonist

92

DNBS colitis (rat)

Nicotine 5 –20 mg/ml þhexamethonium Nicotine 50 mg/ml

93

TNBS colitis (rat)

Nicotine 2.5–250 mg/ml

94

Iodoacetamide jejunitis (rat)

Nicotine 12.5– 250 mg/ml

94

Iodoacetamide colitis (rat)

Nicotine 12.5– 250 mg/ml

95

jeunitis and colitis IL-10 2 /2 mice

Nicotine 12.5 mg/ml

60

IL-10 2/2 mice (bone marrow macrophages)

Carbon monoxide

Decreased colonic damage, decreased LTB4, NOS No augmentation of TNF-a, IL-1b, IL-6 Increased colonic damage and MPO activity Abolition of the harmful effect of cigarette smoke Increased colonic damage and MPO activity Increased ROM production and LTB4 concentration less decrease of GSH Protection Reduced colonic damage and MPO activity Abolition of the beneficial effect of nicotine Increased area of ulceration and MPO activity Dose-dependent bivalent effect (decreased damage at low dose, increased damage at high dose) No effect on NOS, PGE2 and serum IL-1 Increased LTB4 Increased jejunal damage, decreased PGE2 and increased NOS Decreased colonic damage, increased microcirculation No effect on PGE2 and NOS Increased jejunal damage with enhanced somatostatin and intestinal trefoil factor mRNA Decreased colonic damage Inhibition of IL-12 production induced by LPS No effect on IL-6, TNF, nitric oxide

DNBS, di-nitrobenzene sulfonic acid; GSH, glutathione; LTB(4) leukotriene B4; MPO, myeloperoxydase; NOS, nitric oxide synthase; ROM, reactive oxygen metabolites; TNBS, tri-nitrobenzene sulfonic acid.

† daily cigarette dose (harmful effects dominant above 15 cigarettes) † concentration of nicotine in cigarettes (less nicotine and more damage) † other unidentified factors, e.g. genetic factors like the apoE genotype, which is known to determine the sensitivity to smoking in coronary disease.68

Tobacco and IBD 489

smoking beneficial

SB

SB+C

smoking harmful

C

Crohn’s disease Indeterminate colitis Ulcerative colitis Figure 3. A schematic representation of the effect of smoking in IBD according to the type and location of disease. The width of each rectangle indicates the proportion of cases in a consecutive series of 4057 IBD patients. The height of the arrow indicates the magnitude of the effect of smoking on both development and severity of the disease. C, colon; SB, small bowel.

Figure 3 is a schematic representation of the dual effect of smoking according to disease location and phenotype. Smoking has different effects on different targets—the mucus layer, cytokine production, macrophage function and microvasculature. The balance of these various effects is unpredictable and unstable, and this instability might explain the rapidity of the disease response to changes in smoking habits. There is therefore no reason not to suppose that smoking shifts the phenotype of UC and CD—which might be a part of the spectrum of the same disease-to a disease more proximal, more segmental and patchy, more ischaemic, more excavating and— finally—more aggressive. THERAPEUTIC IMPLICATIONS From a therapeutic point of view, the relationship between smoking and IBD leads to a discussion on the therapeutic value of nicotine and the modalities of smoking cessation in UC and CD, respectively. Nicotine as a therapeutic agent in ulcerative colitis Two prospective, randomized, controlled studies have tested the efficiency of nicotine in mild to moderate attacks of UC.69,70 Nicotine was administered through patches, with ascending dosage to a plateau of 22– 25 mg per day, while usual treatment was maintained. Compared to placebo, patients in the transdermal nicotine group had fewer clinical symptoms. Endoscopy in one trial70 and colonic biopsies in the other69 demonstrated a significantly more marked improvement. In another study of patients with left-sided UC that was unresponsive to treatment with a mesalamine enema, additional therapy with 15 mg transdermal nicotine daily was more effective than oral mesalamine, achieving remission in 12 of 15 patients.71 Other studies have used nicotine as nicotine gum, with similar results. As maintenance therapy, transdermal nicotine, 15 mg daily, was found ineffective.72 In most studies, side-effects (nausea, headache, dermatitis) were frequent and tended to overcome the clinical benefit.

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Thus the place of nicotine in the therapeutic armentarium of UC is questionable, although it might be useful in selected cases, particularly in recent ex-smokers with moderate but refractory attacks of UC. Smoking cessation in ulcerative colitis Taking into account the reduced risk for lung cancer and cardiovascular disease in nonsmokers with UC73,74, gastroenterologists should not discourage patients with UC from stopping smoking. However, smokers with UC who plan to stop should be informed about the potential risk of increase in disease activity, without higher shortand mid-term colectomy risk. If such a worsening in the disease course occurs, medical treatment should be strengthened and, if not sufficient, the indication of an immunosuppressive therapy can be considered. The therapeutic value of nicotine replacement therapy in this setting remains to be evaluated. Smoking cessation in Crohn’s disease Smoking cessation has become a major therapeutic goal in the management of CD, particularly in young women and in patients with ileal involvement. However, despite considerable efforts, the proportion of CD patients who stop smoking remains low— about 10%—and relapse rate is high.46 Hilsden et al.75 used a questionnaire to show that patients with CD were no more refractory to smoking cessation that the general population. In the intervention study of our group, predictors of smoking cessation were: a high socioeconomic status, a motivated physician, previous intestinal resection and, in women, use of oral contraceptives. The importance and the duration of cigarette consumption were not predictive.46 The proportion of quitters could be increased by better information, for patients and practitioners alike, on the use of nicotine-replacement therapies and antidepressants, and by instituting an individually based smoking cessation strategy. Information Patients know the risks of smoking to their general health but, until recently, most of them did not make any link between their habit and CD. Similarly, a telephone interview showed that only two of 51 general practitioners in the UK were aware of the adverse association between smoking and CD.76 Many gastroenterologists are poorly convinced of the benefits of smoking cessation and do not put much effort into getting their patients to quit. Thus there is a need for more information on the effects of smoking in CD. Nicotine addiction Smoking is a habit sustained and amplified by a dependency on nicotine. Not only is nicotine very addictive but it also provides pleasure, is a stimulant, stabilizes mood and controls weight by lessening appetite and increasing postprandial thermogenesis. Nicotine withdrawal can be poorly tolerated and related symptoms might last several months. Complications when stopping smoking, such as depression and weight gain, are adequate justifications of the many failures to stop smoking. Weight gain is usually 2.8 – 3.8 kg but can be more in women aged less than 55 and in heavy smokers77; in CD, mean weight gain after 1 year of quitting was 3.7 kg.46 Importantly, weight gain is not usually sustained and can be minimized by diet, exercise and serotoninergic agents.78

Tobacco and IBD 491

Depression is also a major concern. Latent depression is observed in a large proportion of smokers and depression following smoking cessation can be severe.79 Careful monitoring of mood is warranted and antidepressants should be used extensively. These effects of nicotine and nicotine withdrawal should be explained in detail to the patient before determining a smoking cessation strategy. The decision to stop smoking should be taken after a period of reflection during which the information and advice given by health professionals, including the gastroenterologist, is considered carefully.

Nicotine-replacement therapies Nicotine substitution during the first 6 –12 weeks of abstinence is required in heavy smokers and in smokers with high levels of dependency according to the Fagerstrom score. It should be used at an effective dosage and in addition to behavioural and cognitive support, not as a sole therapy. Nicotine replacement therapies are more effective than placebo or no therapy in helping smokers to abstain. According to a metaanalysis80, the respective number of smokers needed to treat to produce one successful quitter at 1 year is 10 –58 with nicotine gum, 9 –15 with a patch, 10 with inhaler and 6 – 7 with a nasal spray.

Antidepressants Serotoninergic agents increase the probability of successful smoking cessation and are used routinely during the first months of abstinence.78,81 Bupropion, a psychotropic inhibitor of dobutamine and noradrenaline recapture, significantly increases the smoking cessation rate in smokers motivated to stop smoking.82 Bupropion is also a promising pharmacotherapy for preventing relapse, particularly for women.83 In these studies, side-effects were minimal but patients with serious medical disorders were excluded and the tolerance of bupropion in CD has not been evaluated. A recent case report has shown that CD improves while patients are taking bupropion, 450 mg daily.84

Smoking cessation strategy A therapeutic strategy to stop smoking should be drawn up for each individual, according to the degree of motivation, the score of tobacco dependency, history of depression, prior attempts to quit and previous CD course. In particular, it should be emphasized that treatments are only effective in smokers who are motivated to stop smoking and the first step is to help the patient to identify that smoking is a problem.85 Attempts to quit are not likely to succeed when the disease is highly active or complicated. However, circumstances like a planned pregnancy, a change of contraception or surgery86 are good opportunities for giving advice. The next step is to support the patient in quitting. Family practice physicians and health psychologists providing a combination of pharmacological and group cognitive behaviour therapy for nicotine dependence can be a great help. Easy access to a smoking cessation programme, which is best conducted by specialized physicians, should be offered, particularly to heavy smokers, but the gastroenterologist should also be involved for two reasons; first, because the digestive disease is the main motivation for quitting and, second, because long-term follow-up and counselling are essential to prevent relapse.

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SUMMARY AND CONCLUSION Smoking modifies the risk of developing IBD, increasing the risk of CD and decreasing that of UC. In an individual genetically at risk for IBD, smoking might be the main factor determining the phenotype of the disease, either UC or CD. In addition, smoking exerts a considerable effect on the course of the disease, improving UC and worsening CD, and smoking cessation is followed rapidly by reversal of the effect. Nicotine, carbon monoxide and possibly other substances of tobacco smoke exert various effects on the synthesis of intestinal mucus, cytokine production, macrophage function and microvasculature. Hence the mechanisms whereby smoking affects the development and the course of the disease are still poorly understood. In UC, nicotine is of modest therapeutic value and smoking should not be encouraged because the increased risks of neoplasia and vascular disease in smokers largely outweigh the benefits. In CD, smoking is harmful and persuading patients to stop smoking is probably the most cost-effective strategy for controlling disease activity. In fact, IBD should be considered as tobacco-related diseases in which the most effective measures are preventive. As Kessler et al 87 pointed out, the best approach is to focus on young people and a comprehensive and effective policy is needed to prevent future generations from becoming addicted to tobacco. By altering the smoking habits of young people we could reduce the incidence of smoking-related diseases, including CD, and decrease its severity.

Practice points † current smoking protects against UC and increases the risk of CD † non-smokers with UC have a more severe colitis but a decreased risk of lung cancer and vascular disease † smokers with CD need more steroids, more immunosuppressants and more operations than non-smokers † smoking cessation improves rapidly the course of CD † nicotine-replacement therapies and antidepressants are useful in heavy smokers motivated to stop smoking

Research agenda † the reasons why smoking has an opposite effect in CD and UC need to be explained † the effect of smoking should be examined accordingly to the genetic background, in particular the NOD2-CARD15 genotype † additional intervention studies of smoking cessation in smokers with CD are required † the therapeutic value of nicotine in UC of recent ex-smokers should be evaluated † the innocuity and the efficacy of bupropion and other antidepressants for helping CD patients to stop smoking should be ascertained

Tobacco and IBD 493

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