Inflammatory bowel disease and smoking. A ... - Wiley Online Library

CLINICAL REVIEW

Inflammatory Bowel Disease and Smoking A Review of Epidemiology, Pathophysiology, and Therapeutic Implications Tanja Birrenbach, MD and Ulrich Böcker, MD

Abstract: The relationship between smoking behavior and inflammatory bowel disease (IBD) is complex. While Crohn’s disease (CD) is associated with smoking and smoking has detrimental effects on the clinical course of the disease, ulcerative colitis (UC) is largely a disease of nonsmokers and former smokers. Furthermore, cigarette smoking may even result in a beneficial influence on the course of ulcerative colitis. The potential mechanisms involved in this dual relationship include changes in humoral and cellular immunity, cytokine and eicosanoid levels, gut motility, permeability, and blood flow, colonic mucus, and oxygen free radicals. Nicotine is assumed to be the active moiety. The differential therapeutic consequences comprise the cessation of smoking in CD and, so far, clinical trials using nicotine in different forms of application for UC. In this article, we review the relationship between cigarette smoking and IBD, considering epidemiological, pathogenetic, and clinical aspects. Key Words: Crohn’s disease, inflammatory bowel disease, nicotine, smoking, ulcerative colitis

increasing rate for females).7 Furthermore, the quota of UC patients with a smoking habit is much lower (11%–23%).3–5,8 A better understanding of the pathophysiological impact of smoking on IBD would help to gain new insight into the etiology and pathology of IBD, and possible therapeutic options for its treatment. Here, we will review the relationship between cigarette smoking and IBD, present the beneficial effects of nicotine in UC, and, by demonstrating the overwhelming evidence of the detrimental effects of smoking on CD, will emphasize the importance of smoking cessation as a therapeutic tool in patients with CD.

SMOKING AND CD Epidemiology

Received for publication April 1, 2004; accepted June 7, 2004. From the Department of Medicine II, (Gastroenterology/Hepatology/Infectious Diseases), Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany. Reprints: Ulrich Böcker, MD, Department of Medicine II (Gastroenterology/Hepatology/Infectious Diseases), University of Heidelberg, Medical Faculty at Mannheim, Theodor-Kutzer-Ufer, D-68135 Mannheim, Germany (e-mail: [email protected]). Copyright © 2004 by Lippincott Williams & Wilkins

Sommerville et al were the first to observe the association between smoking and CD.9 In a case-control study including 82 patients with CD and matched control subjects drawn from general practice lists, they found that patients with CD were significantly more likely to be smokers than the control subjects, and the association was stronger for smoking habit before the onset of the disease than for the current smoking habit (relative risk for smokers 4.8; relative risk for nonsmokers 3.5). Subsequent reports have confirmed the initial observation.4,5,8,10,11 In a large meta-analysis performed by Calkins12 of seven suitable CD studies, the association between smoking and CD was found to be remarkably consistent. The metaanalysis yielded a pooled odds ratio (OR) of 2.0 (95% confidence interval [CI] 1.65–2.47) for smokers compared with nonsmokers and an OR of 1.80 (95% CI 1.33–2.51) for former smokers compared with nonsmokers (Table 1). Other reports have failed to identify a significantly elevated risk of acquiring CD for former smokers.4,5 Regarding a possible dose-response effect, no clear pattern has emerged so far. Persson et al11 have postulated that the effect of smoking on CD might be more pronounced in women, with a 5-fold increased risk for current female smokers of acquiring CD compared with their nonsmoking female counterparts, whereas male smokers had only a slightly increased risk (1.3-fold). However, other researchers could not identify gender differences.4,10 An Italian study even claimed the opposite result, with the risk of CD associ-

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he precise etiology of the inflammatory bowel diseases (IBDs) Crohn’s disease (CD) and ulcerative colitis (UC) remains unknown. Even though the two entities share many clinical features, there are differences regarding site, extension, and histologic findings. Another striking distinction is the association with smoking behavior. While CD is associated with smoking and a detrimental effect of smoking on the course of CD is demonstrated, UC is largely a disease of nonsmokers and former smokers, and smoking has a beneficial influence. About 50% (range 39%–72%) of CD patients are smokers,1–5 mostly young women,6 and in contrast, the percentage of the adult population consuming tobacco is lower (eg, in Germany, 31% for women and 39% for men, with an


TABLE 1. Pooled ORs and 95% CIs for Smokers and Former Smokers Compared with Lifetime Nonsmokers for CD and UC Studies Included in Meta-analysis by Calkins12 CD

Nonsmokers Smokers vs nonsmokers Former vs nonsmokers

UC

OR

CI

OR

CI

1.0 2.0 1.8

1.65–2.47 1.33–2.51

1.0 0.41 1.64

0.34–0.48 1.36–1.98

ated with being a smoker holding statistical significance only in males.8

Impact on Disease Behavior and Clinical Course Holdstock et al13 were the first to report that smokers with CD colitis experienced more relapses and more severe pain than their nonsmoking counterparts, and that smokers with small bowel CD tended to have a higher probability for hospitalization and the need for surgery than did nonsmokers. There is now ample information on the detrimental effect of smoking on the clinical course of CD (Table 2). Smokers have reported significantly more days troubled by symptoms than nonsmokers,14 and women smokers documented a lower quality of life than those of women not consuming tobacco.15 In terms of the risk of recurrence or relapse, a deleterious effect of smoking has consistently been observed. Cottone et al found smoking to be an independent risk factor for the development of clinical (hazard ratio 1.46), surgical (hazard ratio, 2.0), and endoscopic recurrence (OR 2.2) in a group of 182 patients who had undergone surgery for CD over a period of almost 20 years.16 An increased severity of clinical and endoscopic recurrence for smokers was noted. The outcomes of former smokers were similar to those of nonsmokers. Different

TABLE 2. Detrimental Effects of Cigarette Smoking on CD • Lower quality of life documented in smoking females • Increased risk of development of clinical, surgical, and endoscopic recurrence • Increased severity of clinical and endoscopic recurrence • Higher risk of early surgery • Adverse effects on the need for corticosteroids and immunosuppressive therapy • Poorer response rate and shorter duration of response to therapy with infliximab • Progression of inflammatory to stricturing or fistulizing disease; more fistulae and abscesses • Risk factor for osteoporosis in women with IBD

© 2004 Lippincott Williams & Wilkins

Inflammatory Bowel Disease and Smoking

reports have supported these findings.6,17–19 A recent study emphasized the importance of smoking cessation to reduce the risk of reoperation for recurrent CD.20 Cosnes et al21 could only affirm an increased risk for the need of surgery in patients who smoked and did not receive immunosuppressive therapy. However, starting smoking after diagnosis was associated with a higher risk of operation. In another study, smoking at diagnosis was related to a higher risk of early surgery only in ileal CD, not in colonic CD.19 Timmer et al1 postulated current smoking to be associated with a 2-fold risk of relapse (defined as an increase of the CD activity index) compared with nonsmoking in a cohort of CD patients who were in remission, which had been partly medically induced. Again, the outcomes of former smokers were similar to those of nonsmokers. Similar results were demonstrated by Duffy et al22 and Cosnes et al.23 Smoking adversely affects the need for corticosteroid and immunosuppressive therapy.21,23,24 Some authors claim a dose-response effect for the daily number of cigarettes consumed,16,18,25 particularly for women,6,17,21 while others do not.1,26 A recent study by Cosnes et al27 demonstrated smoking to be more harmful to female CD patients than to male patients, with earlier and more severe disease. Certain findings point to ethnic differences for the postulated detrimental effects of smoking on CD. In an Israeli study, no association between tobacco consumption and the need for operation, corticosteroid and immunosuppressive medication, hospitalizations, or disease severity could be elucidated, which is consistent with the lack of epidemiological association between smoking and CD in Israel.26 A Spanish study including 63 CD patients and using first-degree relatives as control subjects also failed to detect an association regarding operations, hospitalizations, relapses, and smoking.28 Moum et al29 reported no excess risk of relapse or surgery in smokers in Norway compared with nonsmokers or former smokers. The need for surgery as well as the number and type of complications after surgery was not related to a smoking habit in a group of Spanish CD patients, although recurrence of disease occurred earlier in smokers than nonsmokers.30 Cosnes et al23 noted no increase in the risk of operations or anoperineal complications related to smoking during a median follow-up period of 29 months. Regarding the behavior and localization of CD, smoking has been associated with a higher risk of ileal disease18,19 and less colonic involvement,2,24 which is an interesting fact, given the protective evidence of smoking on the development of UC. However, Cosnes et al failed to note a difference regarding site of disease.21 In Jews, tobacco use was shown to be related to fistulizing disease.31 Tobacco consumption was associated with a decline in the prevalence of inflammatory CD during the early phase of disease, suggesting that smoking may influence the progression of inflammatory disease to stricturing or fistulizing disease.32 Louis et al33 confirmed the association of smoking habit and the development of penetrating behavior.

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More fistulas and abscesses had already been described in smokers than never-smokers by Lindberg et al.18 In terms of responsiveness to anti-inflammatory medication, a recent study revealed that not smoking, compared with smoking, was associated with a higher rate of response and a longer duration of response to infliximab, a monoclonal antibody targeting tumor necrosis factor (TNF)-␣.34 Besides the deleterious effects already mentioned, smoking was found to be an independent risk factor for osteoporosis in women with IBD,35,36 possibly by accelerating the hepatic metabolism of estrogen. The mechanisms by which smoking influences disease presentation and clinical course yet remain to be elucidated. However, given the above information regarding the general harmful effect of smoking on the cardiovascular system and cancer prevalence, patients with CD should emphatically be dissuaded from smoking to reduce the risk of recurrence and the need for immunosuppressive therapy. Special emphasis should be put on smoking cessation in the postoperative setting to reduce the risk of reoperation, as it is probably in this case that smoking cessation is the most beneficial.

rather than to etiology or pathogenesis. His observation was confirmed by Harries et al40 in 1982, who, in a survey about nutritional aspects of IBD, counted only 8% of 230 patients with UC to be current smokers compared with 44% of the matched control subjects (patients with CD or a cohort evaluated for fractures in an orthopedic department). For more than 2 decades, numerous reports from all over the world have confirmed this association. In a meta-analysis including nine suitable case-control studies, the pooled OR of current smokers compared with nonsmokers was calculated to be 0.41 (95% CI 0.34–0.48).12 When the analysis was reversed, with nonsmoking as the risk factor for acquiring UC, the lifetime risk of nonsmokers was 2.9 (95% CI 2.6–3.2). The authors also postulated a higher risk for former to nonsmokers with a pooled OR of 1.64 (95% CI 1.36–1.98) (Table 1). Furthermore, they found a dose-response relationship with an overall pattern of decreasing the risk of disease with increasing the level of smoking. Subsequent studies either supported the data41 or failed to recognize a dose-response relationship.42 Additional supportive evidence was published in different cohort studies. Vessey et al43 reviewed a cohort of 17,032 women in the Oxford Family Planning Association contraceptive study and found a decreased incidence of UC among women who were smokers at the time of entry into the cohort compared with nonsmokers. Samuelsson et al44 studied 98% of all prevalent cases of UC diagnosed in Uppsala County (Sweden) from 1945 to 1964 and also found UC patients less likely to be current smokers than control subjects. Mortality figures from 109 patients with UC in Birmingham showed a relative absence of smoking-related diseases at autopsy.45 Furthermore, two population studies gathered supportive information. In the Mormon populations in Britain and Ireland, who are strongly discouraged from smoking, Penny et al46 found a 5-fold increased risk of UC, whereas no differences regarding CD were noted. In a review of 56 epidemiological studies in Sweden carried out between 1930 and 1990, Tysk and Järnerot47 demonstrated that the sex distribution in UC had changed from an earlier female predominance to a later male predominance. Correspondingly, a changing pattern of adult smoking behavior was noted, replacing the previous male predominance with a female predominance. In pediatric (nonsmoking) series, no changes in the gender distribution were seen, supporting the conclusion that smoking may be protective against UC.

Impact of Cessation of Smoking on the Course of CD To evaluate the benefit of smoking cessation on the course of CD, a large intervention study was performed by Cosnes and coworkers.23 Of 474 smokers with CD, 12% remained abstinent for more than 1 year (ie, quitters). Smoking cessation showed a beneficial effect on the course of CD. The risk of flare-ups in quitters was not different from that in nonsmokers and was significantly lower than that in continuing smokers. The need for steroids and for the introduction or reinforcement of immunosuppressive therapy was similar in quitters and nonsmokers, and increased in continuing smokers. No differences were found regarding the risk of anoperineal complications or the need for excisional surgery during the median follow-up period of 29 months. Regarding these results as well as the general health hazards induced by smoking, and considering the fact that patients with CD seem to be unaware of the risk that smoking has on their disease,37 smoking cessation should be emphasized as a major component in the management of CD. Especially, since patients with CD were found to be no more refractory to smoking cessation than the general population.38

SMOKING AND UC Epidemiology In 1976, Samuelsson39 was the first to observe the negative association between smoking and UC. Regarding the epidemiological aspects of UC, he noted a lack of smokers among UC patients compared with matched control subjects, but attributed this observation to interaction with medication

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Impact on Clinical Course As UC mainly is a disease of nonsmokers and former smokers, there is substantial evidence that smoking alleviates the clinical course of UC. In a group of 30 intermittent smokers with UC, resuming smoking over a 6-week period led to an improvement of symptoms in 50%. The members of this group smoked about 20 cigarettes daily, compared with 10 smoked daily by those who © 2004 Lippincott Williams & Wilkins



did not improve.48 In a study including 51 patients with UC who were in clinical remission, 28 patients believed that smoking improved their symptoms, and none felt that smoking had a detrimental effect on their disease.49 Male patients with UC who continued smoking moderately were found to report fewer bowel complaints than their nonsmoking counterparts.15 Boyko et al reported a lower hospitalization rate in patients who were smoking at the onset of UC, but could not identify a difference in the colectomy rate between smokers and nonsmokers.50 By contrast, another study noted a higher colectomy rate in nonsmokers and ex-smokers and also found fewer relapses in patients who began smoking after diagnosis.28 However, the clinical relapse rate as well as the number of hospitalizations were similar. A retrospective analysis in France showed that smokers required oral steroids less often and had a lower actuarial colectomy rate.51 In a subgroup of patients with limited disease at onset of symptoms, the percentage of smokers developing pancolitis was lower than that among nonsmokers. In a study in Israel, smokers were found to have less extensive disease as well as fewer hospitalizations and operations than nonsmokers.26 No difference was identified regarding the need for treatment with immunosuppressive drugs and corticosteroids. However, some studies failed to identify a beneficial effect of smoking on the course of UC. Holdstock et al13 were unable to identify a clear pattern between smoking and the course of UC, possibly due to the overall low number of smokers in the study. Benoni and Nilsson3 found no association between smoking and colectomy rate, and disease activity. In a Spanish study, the need for operations and the incidence of postoperative complications were not related to smoking habits.30 In Norway, Moum et al29 noted no excess risk for operations or relapse in smokers versus nonsmokers or former smokers, and the risk of relapse did not vary with the level of cigarette consumption. Smoking is strongly associated with the development of cancer, most likely due to the generation of N-nitrosamines.52 Recently, cigarette smoke exposure was found to increase colitis-associated colonic adenoma formation in mice in a dosedependent manner, possibly involving the inhibition of cellular apoptosis by the up-regulation of bcl-2.53 The investigation of smoking effects on pouchitis is particularly interesting. If pouchitis is perceived as an immunologic reactivation of UC, beneficial effects should be expected. In cases of pouchitis that in fact reflect preoperatively undetected CD, a deleterious impact would be plausible. Therefore, the assignment of a patient with clinical signs of pouchitis to specific subgroups (eg, acute versus chronic, UC reactivation versus CD occurrence) is mandatory for appropriate association studies. To date, there have been conflicting results. Merrett et al postulated that smoking may prevent pouchitis in patients who have undergone restorative proctocolectomy for

UC,54 whereas other studies have failed to support a beneficial effect of smoking on pouchitis.55,56


Impact of Cessation of Smoking on the Course of UC Divergent results were found concerning the impact of smoking cessation on the course of UC. In a study including 32 patients with UC who stopped smoking after the diagnosis of UC, the severity of the disease increased after smoking cessation (increase in the rate of years with active disease, years with hospitalization, and years receiving major medical therapy including oral and intravenous steroids as well as azathioprine). The duration of immunosuppressive therapy with azathioprine was longer in quitters and nonsmokers than in continuing smokers. No impact on the colectomy rate was observed among patients in this limited number of cases.57 By contrast, Fraga et al28 reported no increase in the number of flare-ups in a group of patients with UC who gave up smoking, however, the number of patients was certainly too small (n = 7) to draw any general conclusions.

Temporal Relationship Between Cessation of Smoking and Onset of UC Symptoms Inquiries have been made concerning the time between the abandonment of smoking and the onset of UC symptoms. In 1987, Motley et al reported, that of 107 ex-smoking colitis patients, 52% had developed symptoms within 3 years after the cessation of smoking, with a peak in the first year (mean duration 5.7 years).58 Similar findings have been made by other authors.49,59 Lindberg et al4 found that one third of the former smokers who contracted UC did so within 2 years after stopping smoking, but in many cases the disease emerged several years later (mean duration 6.4 years). In the report by Boyko et al,60 the highest risk for acquiring UC was within 48 to 71 months after quitting smoking, however, again, an elevated risk was also seen 6 years after quitting. It is difficult to conceive a pathogenetic mechanism that would explain the fact that giving up smoking results in a rebound effect regarding the risk of acquiring UC, often lasting several years. If smoking either protects against UC or delays its onset, then one would expect nonsmokers to develop UC at an earlier age than those with a smoking history, a hypothesis that was in fact confirmed for male patients.27,61

Association Between Smoking and Primary Sclerosing Cholangitis Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown cause that is strongly associated with UC. The prevalence of UC in patients with PSC reaches 98%,62,63 whereas a much smaller proportion of patients with UC experience concomitant PSC (3.7%).64 Recently, PSC, like UC, was found to be a disease of nonsmokers, as the odds of having PSC significantly decreased in current

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and former smokers (OR 0.35) compared with never-smokers (OR 0.76),65 confirming previous results by other authors.66,67 The protective effect was independent of whether or not the PSC patient had underlying IBD. The authors demonstrated a greater protection by smoking against developing PSC than UC, postulating that the protective effect of smoking on the development of PSC cannot be attributed solely to the known inverse association between smoking and UC, but is, at least partly, independent of it. However, the mechanisms by which smoking exerts this protective effect on PSC so far remain unknown. Lately, studies using oral and transdermal nicotine in patients with PSC have shown no benefits in terms of symptoms or liver biochemistry.68,69

who smoked were more likely to be average smokers than light smokers. Regarding the usual association between nonsmoking and UC, these findings also were confirmed in the Jewish population. Furthermore, in the pioneer study by Harries et al reporting on the inverse association between smoking and UC, no association between CD and smoking could be found in the Cardiff area.40 Epidemiological data support the notion that genetic factors weigh much heavier in patients with CD than in those with UC, with concordance for CD in identical twins being about 50% and concordance for UC being much lower.76 Therefore, environmental factors might have more of an influence in UC than in CD.

RELATIONSHIP BETWEEN HERITABILITY AND SMOKING HABITS IN IBD The etiology of IBD still remains unknown, but strong evidence implicates genetic and environmental factors. Recently, genetic susceptibility and resistance loci for IBD have been postulated, leading to the identification of mutations in the NOD2/CARD15 gene on chromosome 16 for CD, “genetically” explaining the occurrence of disease in less than 20% of affected patients.70–72 Studies have shown that the percentage of smokers among CD patients with a family history of IBD was not different from the one obtained from CD patients without a family history of IBD, but was significantly higher than that of patients with a familial history of UC.73–75 In a genetically predisposed population, smoking could be an important environmental factor in determining or expressing CD instead of UC. Thus, the protection that smoking exerts on sporadic UC might partly be due to a shift of phenotype to CD rather than UC. However, this effect was seen only in a proportion of cases, indicating that the genetic background usually determines the clinical presentation.75 On the other hand, controversial results regarding the impact of smoking in genetically predisposed cases have been found. In monozygotic twins concordant for CD, the smoking pattern was similar to those who were discordant for CD, suggesting that an identical genetic background in addition to a similar smoking pattern was not sufficient to cause the disease.76 IBD is two to four times more frequent in the Jewish population in various geographic areas, probably due to genetic factors.77–79 Interestingly, studies involving the Jewish population found a lack of the usual association between smoking and CD.26,80–82 In a large multicenter study, no significant difference in smoking habits was found between Jewish CD patients and control subjects, with an OR for CD in current smokers of 1.3 versus clinic control subjects, and an OR of 0.96 versus neighborhood control subjects.81 No significant proportions of ex-smokers or never-smokers were found when comparing CD patients and control subjects. Although no excess of smokers in CD patients was found, CD patients

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ROLE OF PASSIVE SMOKING IN IBD Given the fact that former smokers are at a greater risk of developing UC, one might expect children who have been passively exposed to smoke to have a similar increase in risk. Sandler et al examined the effect of regular exposure to environmental tobacco smoke until the age of 15 years and the risk of UC.83 They found that childhood exposure to environmental tobacco smoke significantly decreased the adult risk of UC (OR of passive smokers in childhood to nonexposed nonsmokers 0.5). There was no distinction made between exposure during childhood and a possible exposure during pregnancy. A relevant time period of exposure could not be isolated. These findings correspond to the results found by Harries et al, stating that patients with IBD more often come from a nonsmoking household.40 Contrary results were seen in a case-control study by Lashner et al, who concluded that passive smoking exposure at birth (OR 3.02) and maternal smoking at birth (OR 2.09) as well as, to a lesser extent, passive smoking exposure at symptom onset (OR 1.88) are associated with an increased risk of developing IBD in children until the age of 18 years.84 The association was stronger in CD (OR 5.32, 2.76, and 2.0, respectively) than in UC (OR 2.19, 1.71, and 1.71, respectively), with a dose-response effect being noted. Since passive smoking at birth was no more harmful if only the mother smoked than if either parent smoked, the toxic exposure was more likely to be inhaled rather than passed through the placenta or transmitted in breast milk. Thus, the effect of exposure to passive smoking in children on developing IBD reflects the same increased risk for developing IBD as in former smoker among adults. Whether these results are obtained by a direct toxic or immune-modulating effect of tobacco smoke, or whether exposure to tobacco smoke may lead to secondary effects, like an increase in pulmonary diseases, remains to be elucidated. In a third case-control study, Persson et al found an increase in the risk of CD by exposure to environmental tobacco smoke during childhood (until the age of 15 years) (OR 1.5), while the corresponding risk of UC gave an OR of 0.98.11 Regarding Jewish patients with IBD, no association between pas© 2004 Lippincott Williams & Wilkins



sive smoking and IBD was noted in a multicenter case-control study in Israel.85 Yet, when a quantitative exposure index was used, UC patients were found to be less exposed to passive smoking than control subjects from their community.

Regarding the maintenance of remission in patients with UC, no beneficial effect of transdermal nicotine therapy (up to 15 mg per 16 hours) compared with placebo over a period of 6 months was noted.99 However, the mean nicotine and cotinine serum concentrations were lower than expected at week 26 (nicotine 5.3 ng/mL; cotinine 62 ng/mL), and thus might have influenced the negative result. Following up 30 patients with remission of distal UC after therapy with either mesalazine plus transdermal nicotine or mesalazine plus oral prednisolone for 12 months, Guslandi100 suggested that nicotineinduced remission of UC lasts longer than that obtained by therapy with oral corticosteroids. Further studies are needed. Adverse events are a concern when nicotine is therapeutically administered. Generally, adverse events were common (>50%), but generally mild. They were more frequently noted in nonsmokers than in ex-smokers. They can be reduced in nonsmokers by initially administering a low-dose patch and subsequently escalating the nicotine dose. Adverse events include contact dermatitis, nausea and vomiting, light-headedness, headache, sleep disturbance, central nervous system stimulation, sweating, tremor, and tachycardia. Addiction was not observed by Thomas et al, which is consistent with the theory that transdermal nicotine application does not lead to the sharp plasma level increases observed after cigarette smoking associated with addiction.99 To reduce the systemic side effects as well as local irritation caused by nicotine patches, the topical administration of nicotine in the form of nicotine enemas or delayed-release oral formulation was tested. The exact site of nicotine absorption after topical administration remains unknown. About 60% of nicotine is converted into its major metabolite, cotinine, on a first-pass effect in the liver, thus reducing high systemic levels of nicotine that cause side effects and enabling a higher local concentration of nicotine. An oral formulation of nicotine-tartrate via a delayedrelease form leads to the reduced bioavailability of nicotine (about 40% compared with 75%–90% using transdermal application), which is probably due to a first-pass effect in the liver.101 In two preliminary studies including patients with active distal UC, liquid nicotine enemas using nicotine-tartrate or carbomer (6-mg nicotine base) were suggested to be of clinical efficaciousness in the absence of detectable serum nicotine concentrations. Adverse events were of minimal consequence. However, the liquid enemas were difficult to retain.102,103 Further controlled trials are needed to determine the therapeutic value of topical nicotine administration.

CLINICAL TRIALS USING NICOTINE IN UC Since approximately 50% of intermittent smokers with UC reported that smoking about 20 cigarettes daily over a 6-week period improved their UC symptoms,48 uncontrolled trials using nicotine gum86 or transdermal nicotine in UC patients were performed.87–89 Chewing polacrilex gum containing up to 4 mg nicotine results in peak blood nicotine levels that are usually observed with cigarette smoking, however, the extraction of nicotine from gum was incomplete and very variable (53%–72%).90,91 Even though some studies have reported a beneficial effect of nicotine gum in some ex-smokers with active UC, no such effect has been seen in nonsmoking patients.86,92,93 Transdermal patches containing nicotine lead to steady plasma nicotine levels that are directly proportional to the nicotine dose received during smoking and lead to peak nicotine concentrations of approximately two thirds of those measured during smoking.94 Yet, compared with smoking cigarettes, no sharp increases in blood nicotine concentrations have been observed using transdermal application. These peaks are probably associated with causing addiction in smokers. Pullan et al treated 72 patients with active left-sided UC with either transdermal nicotine patches or placebo over a period of 6 weeks.95 The standard medication comprising mesalamine (all patients) and glucocorticoids (12 patients) continued to be administered. Most patients tolerated nicotine doses of 15 to 25 mg per 24 hours, leading to plasma nicotine concentrations of 8.3 and 12.1 ng/mL, respectively, and cotinine concentrations of about one third of the values for a smoker smoking about 20 cigarettes per day. Patients in both the nicotine and placebo group improved, yet the improvement in clinical and histologic grades was greater in the group treated with nicotine. Seventeen of 35 patients in the nicotine group had complete remissions, compared with only 9 of 37 patients in the placebo group. Similar results were found by Sandborn et al.96 Transdermal nicotine at the highest tolerable dose of up to 22 mg per 24 hours for 4 weeks led to a clinical benefit in 39% of patients receiving nicotine compared with 9% receiving placebo. No improvement of histology was seen.96 Other trials compared transdermal nicotine therapy (up to 25 mg per 16 hours or 15 mg per 24 hours, respectively) with oral prednisolone therapy (15 mg per day or 30 mg per day, respectively) for 6 and 5 weeks, respectively, in patients with active UC.97,98 No significant differences were found between the two groups, yet there was a trend for the corticosteroid therapy being more efficacious. © 2004 Lippincott Williams & Wilkins

POSSIBLE PATHOGENIC MECHANISMS OF SMOKING ON IBD So far, the exact mechanisms involved in the interaction of smoking and the course of IBD still remain unclear (Table 3). By determining these modes of interaction, we should be

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TABLE 3. Possible Mechanisms in the Pathogenic Interactions of Smoking and IBD

probably due to immune dysfunction caused by abnormalities of phagocytic and neutrophil function, has been discovered.111 The persistence of antigen within the phagocyte leads to granuloma formation. Recently, CARD15 was also identified as an important susceptibility gene for different granulomatosis syndromes like Blau syndrome.112 An altered response to bacteria is now being recognized as a major factor in IBD pathogenesis. Mutations of the leucine-rich repeat sequence of the NOD2/CARD15 gene are more frequently found in CD patients than in UC patients or control subjects, and they seem to be associated with an impaired cellular response to muramyl dipeptide and the reduced production of antimicrobial peptides.70,71 An additional or synergistic effect of smoking on this antibacterial pathway could help to explain the different effects of smoking on UC and CD. Also, there is evidence that smoking influences cytokine levels. Byron et al found an increased production of IL-4 in smokers.113 In vivo and in vitro studies showed that nicotine and smoking lead to a reduction of IL-1␤, IL-2, IL-8, IL-10, and TNF-␣ in peripheral blood mononuclear cells, and of IL1␤ and IL-8 in colonic tissue from control subjects and patients with IBD.114–119 Sher et al postulated a significant reduction of cytokine levels within the colonic mucosa in smokers with IBD, specifically IL-1␤ and IL-8 for patients with UC, and IL-8 for patients with CD.117 In rats, DNBS-induced colonic damage was improved in passive-smoking rats involving changes in colonic cytokine levels.120 The augmentation of leukotriene B4, TNF-␣, IL-1␤, and IL-6 levels was alleviated. In contrast, the deprivation of IL-10 during UC was preserved. The exact meaning of these changes in the cytokine balance still remains poorly understood. Smokers have a greater capacity for the generation of free oxygen radicals, with reduced antioxidant capacity.121 On the other hand, Srivastava et al have suggested that nicotine could decrease neutrophil-mediated inflammation via the inhibition of oxygen free radical production by neutrophils.122 Other reports have discussed the involvement of free radical production and neutrophil infiltration in DNBS-induced colitis in rats.104,123,124 Pre-exposure to cigarette smoke, mimicking active and passive cigarette smoking, significantly enhanced colonic damage involving a further increase in colonic myeloperoxidase activity (an enzyme mainly produced by neutrophils), leukotriene B4 level (postulated to be a promotor of polymorphonuclear leukocyte activation), reactive oxygen metabolite levels, and nitric oxidase synthase activity (an enzyme postulated to induce cytotoxicity as a result of the interaction of nitric oxide with superoxide to produce peroxynitrite, an oxidizing agent). The depressive effect of 2,4,6-trinitrobenzene sulfonic acid (TNBS) on cellular antioxidant glutathione level was further reduced by cigarette smoke exposure. In contrast, increased colonic superoxide dismutase activity after TNBS was attenuated by cigarette smoke exposure, implicating that cigarette smoke exposure decreases the free radical-

• • • • • • • • • •

Modulation of cellular and humoral immunity Changes in cytokine levels Modification of eicosanoid-mediated inflammation Reduction of antioxidant capacity, production of oxygen free radicals Release of endogenous glucocorticoids Colonic mucus effects Alteration of mucosal blood flow Pro-thrombotic effects and promotion of microvascular thrombosis Alteration of gut permeability Modification of gut motility

able to gain new insight into the pathogenesis and possible therapeutic options of IBD. Even though tobacco consists of numerous components, we suspect that the metabolite responsible for the impact on the course of IBD is nicotine. So, in several studies, nicotine, in different modes of application, was found to ameliorate the course of active UC, and in experimental colitis induced by 2,4-dinitrobenzene sulfonic acid (DNBS) in rats, the aggravating effect of exposure to cigarette smoke was demonstrated to be caused by nicotine.104 However, there is no absolute proof of nicotine being the (sole) active moiety. The clinical trials so far have not shown impressive results, and there are other possibilities worth being considered. Macrophages exposed to carbon monoxide showed reduced lipopolysaccharide-mediated secretion of the proinflammatory cytokine TNF-␣ and an increased secretion of interleukin (IL)-10, the former being a pathogenetically important mediator of CD, and the latter being an antagonist of the T-helper 1 cell cytokine profile that is considered to dominate in patients with CD.105 The inhibition of TNF-␣ secretion in this setting was independent of IL-10. Furthermore, in mice exposed to inhalative carbon monoxide heme oxygenase 1 was substantially induced. Heme oxygenase 1 has been associated with decreased tissue damage in various experimental animal models of inflammation.106 We know that smoking modulates the cellular and humoral mechanisms of immunity, also involving the intestinal immune system. Heavy smokers may have reduced levels of immunoglobulin-A in both saliva and intestinal secretions.107,108 Heavy smoking also influences cellular immune-defense mechanisms, leading to a state resembling immune suppression with an increased level of suppressor CD8+ T cells and a diminished ratio of CD4/CD8 T cells, which is reversible after the cessation of smoking.109 Smoking has a deleterious effect on phagocyte function, decreasing their bactericidal and bacteristatic activity.110 The association between glycogen storage disease 1b and CD,

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scavenging activity of colonic tissue. These findings correlate with the deleterious effects of smoking on patients with CD but offer no explanation for the beneficial effects on UC patients. On the other hand, the TNBS experimental colitis model in general resembles more closely the changes observed in CD patients than in UC patients. Lately, the bivalent effects of nicotine on the severity of TNBS-induced colitis were reported on in rats, with small quantities of nicotine reducing the damage and vice versa, which relates to the different effects seen in UC and CD patients.125 Eicosanoid-mediated inflammation also might play an important pathogenetic role. Nicotine was shown to reduce 6-keto prostaglandin F1-␣, prostaglandin F2-␣, as well as hydroxyeicosatetraenoic acid in the rectal mucosa in rabbits.126 Motley et al also could detect a reduction in the levels of colonic mucosal eicosanoids such as prostaglandin E, 6-keto prostaglandin F1-␣, and leukotriene B4, C4, D4, and E4 in healthy smokers compared with those in nonsmokers.127 Recently, experimental findings have indicated that cyclooxygenase-2 might be associated with IBD. Guo et al reported that in TNBS-induced IBD in rats, colonic cyclo-oxygenase-2 was markedly increased and was potentiated further by cigarette smoke exposure, while cyclo-oxygenase-1 did not change. Cyclo-oxygenase-2 inhibitors protected against chemical damage and attenuated the potentiating effect of cigarette smoke exposure on the colic damage.128 Smoking is known to have strong effects on lung mucosa and bronchial mucus hypersecretion. Reports of the effects of smoking and nicotine on colonic mucus vary. Patients with UC are shown to have qualitatively and quantitatively abnormal colonic mucus production.129 Pullan130 has reported a significantly thinner mucus layer in the left colon and rectum in patients with UC compared with healthy (smoking and nonsmoking) control subjects. In patients with CD, the mucus layer tended to be thicker in the colon and rectum than in control subjects. This may be due to the patchy character of CD, with high levels of inflammatory mediators furthering the release of mucin from adjacent “healthy” goblet cells. In rectal biopsy specimens from nonsmoking patients with UC, colonic glycoprotein synthesis was lower than that in smoking patients with UC and control subjects.131 Also, Finnie et al132 found an increase in in vitro mucus glycoprotein secretion in the presence of nicotine. In vivo studies in rabbits showed an increased mucus production in rectal mucosa with high doses of nicotine.126 Yet, no effect of transdermal nicotine on mucin gene expression in UC patients was found by Louvet et al.119 The effect of stress on IBD has long been a subject of controversy. The development of colitis in cotton-top tamarins is restricted to captive populations and is not found in wild tamarins, supporting the hypothesis of the chronic stress of captivity being involved in the expression of the disease. Previous inflammation induced by TNBS rendered the rat colon more susceptible to the effects of stress on enteric nerve func-

tion and increased inflammatory parameters as myeloperoxidase activity and plasma corticosterone in response to stress.133 Colitis induced in mice by DNBS could be reactivated by stress plus a subthreshold dose of DNBS, but not by the administration of DNBS alone. The reactivation process was immune-dependent and involved CD4 T cells.134 The mechanisms through which stress enhances gut inflammation have been little investigated. There is evidence that the central nervous system may modulate aspects of intestinal inflammation through alterations of cytokine activation of the hypothalamus-pituitary-adrenal axis and the resultant glucocorticosteroid release.135 Corticotropin-releasing factor (CRF) is a primary mediator of the hypothalamus-pituitary-adrenal axis response to stress. However, some studies have indicated a protective role rather than a causative role for central CRF against experimental colitis induced by stress.136 The exact meaning of the role of CRF and the consecutive plasma corticosterone responses to stress stimuli still remains to be elucidated. The link between smoking and stress is suggested by the observation that endogenous adrenocorticoid release can be stimulated by smoking.137,138 Another hypothesis to be investigated is whether smokers are more exposed to stress and stress is an independent factor in disease modulation. Taken together, the exact meaning of the interaction of stress, smoking, and the different effects on UC and CD needs to be further addressed and may offer new insights into the pathophysiology of IBD. Patients with UC are reported to have a significantly increased rectal blood flow, and a reduction in rectal blood flow induced by smoking may be one of the mechanisms whereby smoking influences the course of UC.139 Wakefield et al140 suggested multifocal gastrointestinal infarction mediated by chronic mesenteric vasculitis as a possible pathogenetic mechanism for CD. An increase in procoagulant activity and the promotion of microvascular thrombosis related to smoking could have an impact on the course of CD.141 The effect of smoking on gut permeability was discussed by Jenkins et al.142 Patients with IBD were found to have an increased intestinal permeability to chromium-51-labeled ethylenediaminetetra-acetic acid. Smoking was found to decrease the intestinal permeability to chromium-51-labeled ethylenediaminetetra-acetic acid in healthy control subjects.143 Yet, no such observation could be made in smokers with UC compared with nonsmokers with UC,144 refuting the notion that the protective effect of smoking on UC is due to the moderation of an increased intestinal permeability. Nicotine also affects gut motility and increases intestinal motor activity.145,146 In some studies, hexamethonium, a ganglionic blocker, has been shown to decrease the potentiation of DNBS-induced damage by smoking, suggesting that nicotine is at least one active compound of cigarette smoking that is responsible for the changes in inflammatory response and im-


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plicating the involvement of a neural pathway.104 Recently, the first presentation of nicotinic acetylcholine receptors, which were already known to occur in the small bowel, was demonstrated in the colon in a variety of cells, including the mucosal epithelium.147,148 Yet, neither smoking nor nicotine influenced the receptor density or distribution. However, there were indications that patients with UC (smoking and nonsmoking) had a lower density of receptors in the mucosal epithelium, possibly related to an increased cell turnover in UC. A change of the receptor function might be involved in the beneficial effect of smoking on UC. In conclusion, no single mechanism to explain the different effects of smoking on CD and UC has been identified so far. The possible ways of interaction include changes in the immune system on the humoral and cellular level, as well as changes in cytokine levels and modification of the eicosanoidmediated inflammatory response. Furthermore, the generation of oxygen-free radicals and a reduced antioxidant capacity might be of importance, as well as the effect of smoking on the stress response. Colonic mucus effects and the alteration of mucosal blood flow as well as prothrombotic effects, and the promotion of microvascular thrombosis have been discussed. Gut motility and permeability might play a key role in our understanding of the interaction. A reasonable assumption is that it must be connected with the fundamental differences between CD and UC, that is, the location of disease (esophagus to rectum versus colon), the involved bowel wall compartments (transmural versus mucosal), the genetic alterations (NOD2 versus IL-1Ra), and the response to probiotics. There is evidence that it might be linked to the host’s response to luminal bacteria. We like to speculate that the postulated impairment of the host’s antimicrobial capacity from antigen uptake to its complete degradation in CD patients may be additionally hampered by smoking, while in UC patients smoking could enhance the lasting beneficial effects of luminal bacteria on mucosal restitution.

CD, including disease activity, recurrence (especially postoperative), and response to treatment, patients should be strongly discouraged from smoking. Even though progress has been accomplished regarding possible genetic explanations of the etiology of CD and new “biologicals” such as anti-TNF-␣ antibodies have been established, we must include all epidemiological findings and promote their therapeutic consequences, even if they require behavioral changes that are more difficult to achieve than the intake of medication. Clinical data for the nicotine treatment of active UC so far have not offered an impressive breakthrough in new therapeutic options. Apart from a limited use caused by side effects, we hesitate promoting an addictive and carcinogenic agent that has been proven to increase cardiovascular and pulmonary mortality. However, further clinical trials with different delivery systems and defined dosages are required to determine the possible benefits of its application.

CONCLUSIONS In this review, we have explored the association between cigarette smoking and IBD. The opposite relationship of smoking habit with CD and UC so far has not offered us a definite plausible hypothesis concerning the pathogenesis of IBD. Even though much evidence of nicotine being the active moiety has been presented, this assumption still remains to be proven. Potential mechanisms involved include changes in humoral and cellular immunity, eicosanoid levels, oxygen free radicals, colonic mucus, and gut permeability, motility, and blood flow. The CD/smoking and UC/nonsmoking association is a source of misunderstanding among doctors as well as patients, and, in our opinion, strong efforts need to be undertaken to illuminate these facts. Given the compelling evidence of the devastating effect of tobacco consumption on the course of

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