| "text": "This is an academic paper. This paper has corpus identifier PMC2533102\nAUTHORS: J. R. Ingram, J. Rhodes, B. K. Evans, G. A. O. Thomas\n\nABSTRACT:\nBackground. Smoking has a detrimental effect in Crohn's disease (CD), but this may be due to factors in smoking other than nicotine. Given that transdermal nicotine benefits ulcerative colitis (UC), and there is a considerable overlap in the treatment of UC and CD, the possible beneficial effect of nicotine has been examined in patients with Crohn's colitis. Aims. To assess the efficacy and safety of nicotine enemas in active Crohn's colitis. Patients. Thirteen patients with active rectosigmoid CD; 3 patients were excluded because they received antibiotics.\nMethods. Subjects were given 6 mg nicotine enemas, each day for 4 weeks, in an open pilot study. At the beginning and end of the trial, a Crohn's disease activity index (CDAI) score was calculated, sigmoidoscopy was performed, and haematological inflammatory markers measured. \nResults. Mean CDAI decreased from 202 to 153—the score was reduced in 6 patients, unchanged in 3, and increased in one. Frequency of bowel movements decreased in 8 patients and the sigmoidoscopy grade was reduced in 7. Mean C-reactive protein decreased from 22.0 to 12.3 mg/L. There were no withdrawals due to adverse events. \nConclusions. In this relatively small study of patients with active Crohn's colitis, 6 mg nicotine enemas appeared to be of clinical benefit in most patients. They were well tolerated and safe.\n\nBODY:\n1. INTRODUCTIONIt is a remarkable\nepidemiological observation that whilst ulcerative colitis (UC) is related to\nnonsmoking [1–4], the opposite\napplies to Crohn's disease (CD).\nPatients with CD are more often smokers compared with the general\npopulation [5], and smoking has an adverse effect on the course of their\ndisease [6]. Several mechanisms for this could be relevant; components of\ntobacco smoke, such as oxidizing chemicals, which, unlike nicotine, have\nprothrombotic effects, could exacerbate microvasculature abnormalities and\nischaemia of the bowel wall [7]. It has also been suggested that CD could be\ncaused by an impaired host response to luminal bacteria; this, in turn, could\nbe exacerbated by the immunosuppressive effects of smoking on macrophages [8, 9].\nIt is likely that different mechanisms are responsible for the “opposite effects” of smoking in CD and\nUC, which are in many other respects similar diseases. The effects of smoking should not be considered synonymous with nicotine. Nicotine, as opposed to smoking, may have a beneficial effect in patients\nwith Crohn's colitis, given that there is a considerable overlap in the\ntreatments for the two conditions and nicotine has been shown to be of benefit\nin UC. Although the specific mechanisms\nunderlying this effect remain unclear, nicotine has a number of actions that\ncould be potentially beneficial, including effects on the immune system [10]\nand gut motility [11].A recent Cochrane\nReview [12] has confirmed benefit from transdermal nicotine in active UC: a\nmeta-analysis of two eligible randomized placebo-controlled trials [13, 14] so\nfar performed showed that after 4 to 6 weeks treatment, 19 of 71 patients\ntreated with transdermal nicotine were in remission compared to 9 of 70 given\nplacebo (odds ratio 2.56, 95% confidence interval 1.02–6.45). A nicotine enema has also been developed and\nfound to be of benefit when given as additional therapy in two uncontrolled\npilot studies in active distal UC [15, 16], but not in a recent randomised\ncontrolled trial [17]. A phase I-II\ntrial of delayed release oral nicotine has shown promise [18] but a controlled\ntrial is awaited.The aim of this open pilot study was to examine the efficacy and safety of nicotine enemas in active distal Crohn's colitis.2. MATERIALS AND METHODS2.1. PatientsPatients with CD, based on the clinical, endoscopic, and histological features of Lennard-Jones' criteria [19], were recruited from the gastroenterology outpatient department\nof a single centre; the key selection criteria were clinical and sigmoidoscopic evidence of active disease in the rectosigmoid region. Although the presence of CD in other regions\nof the gastrointestinal tract was permitted, the patient's principal clinical problem had to relate to active distal colitis.\nPatients were not enrolled if they were current smokers, had other\nunstable medical problems, were pregnant or lactating, had used enemas in the previous week, had changed their CD therapy with mesalazine, steroids, or antibiotics within the last 2 weeks, or had changed immunosuppressive therapy with azathioprine in the previous 3 months.\nThe dosage of all concomitant medications was kept unchanged during the study period.2.2. Study designThis was an open pilot study of 4 weeks' duration in which nicotine enemas were given as additional therapy—subjects\ncontinued their conventional treatment without change during the study\nperiod. Each 100 mL liquid enema\ncontained 6 mg of nicotine complexed with 400 mg of the high molecular weight polyacrylic acid carbomer, Carbopol 974P (Goodrich, UK), as already described [20]. At the time of enrolment, a record was made\nof the patient's symptoms of colitis including stool frequency, abdominal pain,\ngeneral well being, any complications of CD and urgency of defaecation; the\nlatter was graded as none, mild, moderate, or severe enough to cause\nincontinence. Although Crohn's colitis\nmay be patchy, sigmoidoscopy with a biopsy of the most inflamed area was also performed by the same investigator in each case.Patients were also asked to complete an inflammatory bowel disease quality of life questionnaire (SIBDQ) [21] and blood\ntests were taken for a full blood count, liver and renal function, and\ninflammatory markers.During the study, patients kept a diary of their bowel symptoms and any adverse events (AEs). The\npatients were assessed at the end of the 4-week trial period, or at premature withdrawal, or at any other time at the patient's request. The initial assessments were repeated by the\nsame physician. Sigmoidoscopy with a\nbiopsy, again from the most inflamed area, was repeated.2.3. Outcome measuresThe main outcome measures used were clinical improvement as measured by Crohn's disease activity index (CDAI) [22], and changes in bowel frequency and urgency of defaecation. Urgency was included because it is a useful\nguide to the severity of inflammation in distal colitis. At sigmoidoscopy, the severity of\ninflammation of the worst affected area was graded visually according to the system described by Dick et al.\n[23]. The biopsy specimens were stained\nwith haematoxylin and eosin and graded by one histopathologist (GTW) according\nto the Truelove and Richards system [24] adapted for Crohn's colitis; see Table 1.2.4. Ethical considerationsThis study was\napproved by the Bro Taf Local Research Ethics Committee.3. RESULTSOf the 13 patients recruited, 3 were excluded because they were also given antibiotics for a chest\ninfection, a middle ear infection, and recurrence of a finger infection during the study period. Demographic details of\nthe remaining 10 patients are in Table 2; 7 were male and the mean age was 52\nyears. Seven patients were exsmokers whilst the remainder had never smoked.The mean duration of disease relapse was 45 weeks and in 4 patients was greater than 99 weeks. Half of the\npatients were on concomitant oral 5-ASAs, 2 were on prednisolone (10 mg) and 2 were on azathioprine; several patients had been intolerant of thiopurines. Only one patient had recently taken enemas,\nasacol foam. The mean baseline CDAI\nscore was 202 (SD 80, range 73 to 348).\nIn addition to their colonic involvement, one patient also had small\nbowel CD. Three patients had disease\nlimited to the left side of the colon.3.1. EfficacyPatient 10 withdrew from the study after only 2 weeks due to failure to respond to treatment, but was kept in the intention-to-treat analysis; she had the highest CDAI score (348) at baseline; all other patients completed 4 weeks' treatment. Changes in the main outcome\nmeasures for each patient are in Figure 1.\nThe mean CDAI score decreased from 202 to 153—the score was\nreduced in 6 patients, unchanged in 3, and increased in one patient. The frequency of bowel movements each day was\nreduced in 8 patients and unchanged in 2, and the urgency to defaecate was reduced in 7 patients, in one case from severe to nil, and was unchanged in the other 3. The sigmoidoscopy score improved in 7 patients and was unchanged in 3, but changes in histology showed no clear trend with a wide variation in the baseline scores.One of the two patients taking oral steroids improved sufficiently to consider a gradual reduction of the dose\nafter the study.The mean SIBDQ score increased from 39 to 47.Mean\nlevels of the inflammatory markers C-reactive protein (CRP), erythrocyte sedimentation\nrate (ESR), and fibrinogen all fell from 22.0 mg/L, 19.1 mm/h, and 4.4 g/L,\nrespectively, to 12.3 mg/L, 12.5 mm/h, and 4.0 g/L, respectively, whilst the mean white cell count was unchanged at 8.4 × 109/L and the mean\nplatelet count increased slightly from 310 to 320 × 109/L. Renal function and liver function tests were unaffected.The effect of disease location on outcome was briefly considered. The only patient with ileal disease improved\nduring the study, with a CDAI reduction from 150 to 74. Of the 3 patients with disease restricted to the left colon, one improved, one remained the same, and the other deteriorated;\nthe respective changes in CDAI score were from 144 to 67, from 348 to 345, and from 156 to 189. In terms of the\nduration of disease relapse, of the 4 patients who had been in relapse for more than 99 weeks, 3 improved, with CDAI changes from 272 to 169, from 200 to 64, and from 150 to 74, whilst one remained the same, with a CDAI change from 73 to 71.3.2. SafetyEight of the 10 patients experienced an adverse event but none were classified as serious.In total, 12 AEs were reported (Figure 2) and 11 of these were thought to be related to nicotine, the other being a localised\nskin rash that resolved spontaneously.Two-thirds of the AEs occurred on commencement of treatment and were\ntemporary, lasting 2 days or less.The\nmost common AE was difficulty sleeping, which included vivid dreams, reported by 4 patients. The other AEs were lightheadedness, nausea, and headache.4. DISCUSSIONThese are the first observations of topical nicotine in patients with active Crohn's colitis. In the 10 patients, there was a\nCDAI reduction in 6 and an increase in one; the mean score decreased from 202 to 153. Frequency of bowel movements was\nreduced in 8 patients, urgency to defaecate was reduced in 7, and the\nsigmoidoscopy score improved in 7; the mean SIBDQ score increased from 39 to 47. Clinical improvement was noted in\npatients who also had disease in locations other than the rectosigmoid,\nincluding the one patient with small bowel disease.Three of the 4 patients with chronically active disease for more than 99 weeks improved. There were no serious AEs and no premature withdrawals due to\nintolerance.A relatively small open pilot study of this nature can only provide preliminary data on efficacy and safety. Hence, although our\nobservations suggested improvement in most of the patients, and certainly no overall deterioration, the findings will need to be corroborated by larger randomised controlled studies. Formal\ntests of significance were not performed because, in this relatively small study, they may have been misleading.\nInitially, it was planned to recruit 20 patients to the study, but\nrecruitment was slow for two main reasons; 10 patients with active Crohn's colitis, who were identified as suitable for entry to the study, were current smokers and therefore excluded. In\naddition, because the study preparation was an enema, those patients whose principal symptoms were related to left-sided active colitis were\ntargeted. However, identifying such a\nhomogenous group proved hard, as a number of patients screened had to be\nexcluded because they had symptoms that related primarily to other sites of disease involvement. This may have\nreduced potential sources of error from our study, but it will probably make it difficult to recruit sufficient numbers to achieve a larger study of homogeneous patients, as defined by the Vienna\nclassification [25]. For this small\npilot study, full Vienna classification of patients was not performed and subgroup analyses were avoided.It is noteworthy that methods used to assess the response of Crohn's colitis to treatment have some limitations. The patchy nature of\nCrohn's colitis means sigmoidoscopy and histology findings should be\ninterpreted with caution. The separate\nrecording and analysis of stool frequency and urgency of defaecation was an attempt to assess some of the more troublesome symptoms of distal colitis, although a contribution from more proximal disease cannot be excluded. This was used in addition to the global\nassessment provided by the CDAI, the more conventional composite scoring system of disease activity that contains systemic features less relevant to this study. Two of the 10 patients had a CDAI\nscore less than 150 at study entry, which might imply disease remission;\nhowever, all patients had rectosigmoid inflammation on sigmoidoscopy and had\nsymptoms of active distal disease.The negative\nassociation between smoking and CD raises questions about whether topical\nnicotine is an appropriate treatment for patients with Crohn's colitis. However, this was justified on the basis that\nthe treatments for UC and CD are very similar, and transdermal nicotine has\nbeen found to provide benefit in UC. It\nis possible that the detrimental effect of smoking on CD is mediated through\nmechanisms independent of nicotine; these could, for example, include\nexacerbation of underlying ischaemia of the bowel wall at the microvascular\nlevel [7] due to prothrombotic oxidizing chemicals present in tobacco\nsmoke. It has also been suggested that\nCD could be caused by an impaired host response to luminal bacteria; this, in\nturn, could be exacerbated by the immunosuppressive effects of smoking on macrophages [8, 9]. These effects could\nmask any benefit from nicotine in Crohn's colitis. It is also possible that the response to\nnicotine differs between ileal and colonic diseases. Rectal enema treatment of the transmural\ninflammation of Crohn's colitis is not well described in the literature,\nhowever it is used in clinical practice.Possible\nmechanisms for a therapeutic effect of topical nicotine in distal colitis\ninclude alterations in colonic motility.\nNicotine has been shown to reduce tone and muscular activity in the\nsigmoid colon [11], an effect mediated primarily through nitric oxide that is\nreleased by nicotine [26]. Another\npotential mechanism is via a reduction in mucosal tumour necrosis factor\n(TNFα), a key cytokine in the generation of inflammation in CD [27]. Nicotine has been found to reduce the secretion of TNFα from macrophages, by activation of α7 nicotinic acetylcholine receptors [28].Our pilot study has shown that, in the 10 patients with active Crohn's colitis, 6 mg nicotine\nenemas were associated with clinical improvement in the majority of patients,\nthey were safe and well tolerated, and did not appear to worsen the\ncondition. 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