Risk-benefit assessment of drugs used in the treatment of inflammatory bowel disease.

Although the aetiology of inflammatory bowel disease remains elusive, many agents are available for the control of symptoms and inflammation. Knowledge of drug pharmacology, indications and side effects is essential to ensure the best possible clinical care while minimising toxicity and inappropriate use. Sulfasalazine consists of sulfapyridine linked to mesalazine (5-aminosalicylic acid) via an azobond. Its use is indicated in the treatment of mild to moderately active ulcerative colitis and in the prevention of relapse in patients with quiescent disease. Patients with mild to moderate colonic or ileocolonic Crohn's disease also benefit from this drug, as do a proportion of patients with isolated small bowel disease. Sulfasalazine has not been uniformly effective in preventing relapse in Crohn's disease, although many clinicians continue its use in patients who respond initially. A high incidence of side effects which limit therapy include intolerance, hypersensitivity reactions and impairment of male infertility. The newer aminosalicylates offer targeted delivery of mesalazine to the bowel, with fewer side effects. Topical mesalazine has proved extremely effective in patients with distal ulcerative colitis; oral forms are effective in the treatment of mild to moderately active ulcerative colitis and in relapse. Both types appear to be effective in the treatment of Crohn's disease, and possibly in preventing relapse. There is no current clinical advantage of one mesalazine preparation over another, nor is there an indication for their use in sulfasalazine-treated patients who have satisfactory response without adverse effects. Corticosteroids are indicated for more severe disease activity where the aminosalicylates have limited efficacy-specifically to induce remission in patients with severe or refractory ulcerative colitis or Crohn's disease. They should not be used to maintain disease remission or in the prevention of postoperative recurrence. Topical corticosteroids allow their local use in distal colitis with minimal systemic side effects. Long term use is limited by side effects, many of which are dose related, although alternate-day therapy may lessen the incidence. Immunosuppressive agents are beneficial for the treatment of refractory inflammatory bowel disease unresponsive to other medications, and may also facilitate the withdrawal of steroids in refractory patients. Mercaptopurine has an added benefit in the treatment of Crohn's disease fistulae; the role of cyclosporin in bowel disease has not been established and its use cannot currently be recommended. The potential toxicity of immunosuppressive agents warrants careful consideration of their use by both physician and patient. Metronidazole is indicated for the treatment of mild to moderate Crohn's disease, including perineal disease. Common side effects include peripheral neuropathy and nausea.(ABSTRACT TRUNCATED AT 400 WORDS)     

Immunosuppressive drugs in inflammatory bowel disease. A review of their mechanisms of efficacy and place in therapy

Immune effector mechanisms are central to the disease process in inflammatory bowel disease, but it is not clear whether the mucosal or systemic immunological abnormalities are primary phenomena, or are secondary to disease activity. Corticosteroid drugs remain the most effective treatment for active disease, but there is no evidence that they are useful for maintenance therapy. Some patients, however, are dependent on low-dose corticosteroids, and relapse when the drug is withdrawn. These drugs have widespread actions on the immune response, and monocytes are particularly sensitive to corticosteroids. In contrast, sulphasalazine and 5-aminosalicylic acid are effective in maintenance therapy, but do not act primarily by immunosuppressive mechanisms. They are effective in maintenance therapy of ulcerative colitis, and mild relapses of ulcerative colitis and colonic Crohn's disease. New preparations of 5-aminosalicylic acid have reduced side effects, many of which are due to sulphapyridine. Azathioprine and 6-mercaptopurine are used less widely: in Crohn's disease there is reasonable evidence for benefit in chronic active disease unresponsive to corticosteroids, and maintenance of remission. In ulcerative colitis, the position is less clearcut. Overall, trials favour an effect in chronic active disease, and there are pointers to an effect in maintenance of remission. Because of their side effects, in particular marrow suppression, these drugs should be reserved for second-line therapy. Similarly, other cytotoxic drugs are not used because of their side effects. More recently, cyclosporin A, with its selective action on interleukin-2 release and/or synthesis, and inhibition of helper T cell function, has been shown to be helpful in Crohn's disease. At present it should only be used in controlled trials, for patients with unresponsive disease in whom surgery is contraindicated. Renal toxicity may limit long term use. There is little data for cyclosporin A in ulcerative colitis. On the basis that there may be an underlying immune defect in Crohn's disease leading to mucosal inflammation, immunostimulant therapy has been used, but there is no evidence for benefit from treatment with BCG or levamisole in active disease or in maintenance therapy. 7S-Immunoglobulin, plasmapheresis or T-lymphocyte apheresis have been used in acute relapse, but evidence is anecdotal, and does not support their use except as a desperate measure to avoid surgery. Further well-designed controlled trials are needed to define the role of all these drugs, and further research into the mechanism of action on the immune response may shed light on the pathogenesis of inflammatory bowel disease.     

Efficacy and tolerability of oral iron therapy in inflammatory bowel disease: a prospective, comparative trial

BACKGROUND: In patients with inflammatory bowel disease, oral iron is anecdotally reported to be less effective and less well tolerated than in those without inflammatory bowel disease, and to increase disease activity. AIM: To study prospectively the effects of oral iron in patients with and without inflammatory bowel disease. METHODS: Patients with ulcerative colitis, Crohn's disease and non-inflammatory bowel disease controls, all with iron deficiency anaemia, were assessed with symptom diaries, a quality of life questionnaire (Inflammatory Bowel Disease Questionnaire; inflammatory bowel disease patients only) and blood tests to measure iron repletion, disease activity and antioxidant capacity before and after starting 4 weeks of oral iron. In patients with ulcerative colitis, sigmoidoscopic scoring and rectal biopsies for reactive oxygen metabolite production were performed before and after iron therapy. RESULTS: All groups showed increases in haemoglobin and ferritin. Iron intolerance occurred in about a quarter of patients in each group. Two of 33 (6%) of inflammatory bowel disease patients had a relapse during treatment. Symptoms worsened in ulcerative colitis, but not in Crohn's disease or non-inflammatory bowel disease patients; Inflammatory Bowel Disease Questionnaire scores improved in ulcerative colitis. Laboratory markers of disease activity, sigmoidoscopic scores, histological scores, antioxidant capacity levels and reactive oxygen metabolite production did not change. CONCLUSIONS: Oral iron is equally efficacious and well tolerated in inflammatory bowel disease and non-inflammatory bowel disease patients. A tiny minority of inflammatory bowel disease patients relapse in association with use of oral iron therapy.     

Granulocyteaphaeresis in steroid-dependent inflammatory bowel disease: a prospective, open, pilot study

BACKGROUND: Uncontrolled studies suggest that granulocyteaphaeresis might be useful in the management of active ulcerative colitis. AIM: To assess the efficacy of granulocyteaphaeresis treatment in active steroid-dependent inflammatory bowel disease. METHODS: We conducted a multicentre, prospective, open, pilot study in patients with steroid-dependent inflammatory bowel disease. All patients were started on 60 mg/day of prednisone; after 1 week, a five-session programme of granulocyteaphaeresis (once per week) was started. The steroid dose was tapered weekly if there was clinical improvement. Remission was defined as an inactive clinical activity index together with complete withdrawal of steroids at week 6. The patients were followed up for at least 6 months or until disease relapse. RESULTS: Twenty-six patients (14 ulcerative colitis, 12 Crohn's disease) were included. More than a half had been previously treated with immunomodulators. Remission was achieved in 62 and 70% of ulcerative colitis and Crohn's disease, respectively. During a median follow-up of 12.6 months, six of eight ulcerative colitis patients maintained their clinical remission; however, only one Crohn's disease patient remained in remission after the first 6 months of follow-up. CONCLUSIONS: Granulocyteaphaeresis is a safe treatment option in inflammatory bowel disease. A five-session programme of granulocyteaphaeresis seems to be efficient in the treatment of steroid-dependent ulcerative colitis, but not in Crohn's disease.     

Anti-TNF alpha therapy in the management of extraintestinal manifestation of inflammatory bowel disease

Inflammatory bowel disease, Crohn's disease and ulcerative colitis, are immune-mediated disorders of unknown etiology that primarily affect the gastrointestinal tract. In addition, other organ systems can be involved such as joint/bones, skin, eyes, hepatobiliary tract, lungs and kidney. Overall, they represent extraintestinal manifestations of inflammatory bowel disease and may present before, in conjunction or after the onset of bowel disease. Extraintestinal manifestations are observed in 20-40% of patients and frequently have a negative impact on quality of patients' life. Some extraintestinal manifestations such as arthritis, erytema nodosum, pyoderma gangrenosum, iritis, uveitis have a pathogenic tumor necrosis factor alpha-dependent mechanism common with Crohn's disease and ulcerative colitis. Early recognition and treatment of extraintestinal manifestations can minimize potential severe complications. In this review we provide an overview on the prevalence and clinical aspects of the more commonly reported extraintestinal manifestations of Crohn's disease and ulcerative colitis and the role of tumor necrosis factor alpha inhibitors in their treatment.     

Prolonged-release mesalazine: a review of its therapeutic potential in ulcerative colitis and Crohn's disease

Prolonged-release mesalazine (Pentasa) consists of ethylcellulose-coated microgranules from which mesalazine (known in the US as mesalamine) is released in the small and large intestine in a diffusion-dependent manner. Dose-dependent improvements in clinical and endoscopic parameters have been reported with prolonged-release mesalazine 2 and 4 g/day in clinical trials in patients with mild to moderately active ulcerative colitis. Induction of clinical and endoscopic remission was achieved in more patients receiving a daily dosage of 4 g/day than in those receiving placebo. In patients with ulcerative colitis in remission, prolonged-release mesalazine is effective in reducing the rate of relapse. Higher dosages tend to be more effective, and a 12-month remission rate of 64% has been reported for patients treated with a 4 g daily dosage of this formulation. Comparative data indicate that prolonged-release mesalazine has similar efficacy in maintaining remission to molar equivalent doses of sulfasalazine. Data from a study in patients with mild to moderately active Crohn's disease indicates that higher dosages (4 g/day) of prolonged-release mesalazine are more effective than placebo in reducing disease activity. After 16 weeks' treatment, 64% of patients receiving a 4 g/day dosage experienced clinical improvement and 43% attained remission. In studies of patients in remission of Crohn's disease, the formulation appears to be more effective in preventing relapse in patients with isolated small bowel disease than in those with colonic involvement. The tolerability profile of oral prolonged-release mesalazine is similar to that of placebo and the incidence of adverse events does not appear to be dose-related. Nausea/vomiting, diarrhoea, abdominal pain and dyspepsia occur most frequently, although their incidence is low. Reports of nephrotoxicity during prolonged-release mesalazine treatment are rare. Conclusions: Oral prolonged-release mesalazine is effective for maintenance and induction of remission of mild to moderately active colitis, both in patients with distal disease and in those with pancolitis. The formulation has similar efficacy to that of equimolar concentrations of sulfasalazine. Prolonged-release mesalazine also appears to be effective in the treatment of Crohn's disease, and maintenance therapy is of particular value in patients with isolated small bowel involvement. Evidence suggests that higher dosages (3 to 4 g/day) of prolonged-release mesalazine have additional therapeutic benefits over lower dosages in patients with inflammatory bowel disease without increasing the incidence of adverse events.     

Pharmacokinetics of a 5-aminosalicylic acid enteric-coated tablet in patients with Crohn''s disease or ulcerative colitis and in healthy volunteers

An Eudragit-L coated oral 5-aminosalicylic acid (5-ASA; mesalazine) product (Mesasal), has been formulated to deliver 5-ASA to the distal small bowel and colon for the treatment of inflammatory bowel disease. The purpose of this study was to compare the pharmacokinetic profile of this drug between two patient groups, with either inflamed small or large bowel and with volunteers. Two carefully selected patient groups (one with nine patients suffering from Crohn's disease restricted to the small intestine, and one with ten patients suffering from total ulcerative colitis) and a group of ten volunteers received two 250 mg Mesasal tablets in the morning, on a fasting stomach. Plasma 5-ASA and acetyl-5-ASA concentrations were followed for 48 h, and urine and faecal excretion for 72 h. There was a great variation in most pharmacokinetic parameters within each group. Numerically, however, the data suggests a somewhat higher systemic absorption in patients with Crohn's disease than in healthy volunteers or patients with ulcerative colitis. The location of the inflammatory process might have some influence on the pharmacokinetics of 5-ASA in inflammatory bowel disease.     

Commonalities and differences between Crohn's disease and ulcerative colitis: the genetic clues to their interpretation

Traditional knowledge of clinical, laboratorial, and endoscopic orders regarding ulcerative colitis and Crohn's disease has begun to be implemented by the revolutionary data from genetic studies. Ever since many decades ago it has been clear that inflammatory bowel diseases are complex multifactorial disorders wherein gut-confined and/or environmental factors must synergize with genetic components to effect the full-blown disorder. The sequencing of the human genome and the generation of public resources of single nucleotide polymorphisms permitted the conduction of powerful population based genome-wide association studies. The latter have increased the number of the identified susceptibility loci to 99. In this review we touched on two pathways that make true susceptibility genes for inflammatory bowel diseases; gene loci that confer specific risk for ulcerative colitis and Crohn's disease were discussed in detail.     

Budesonide: teaching an old dog new tricks for inflammatory bowel disease treatment

Crohn's disease and ulcerative colitis are chronic relapsing inflammatory bowel diseases with extremely great variability in presentation and clinical course. For many decades, corticosteroids and aminosalicylates have been the mainstay of the treatment for both Crohn's disease and ulcerative colitis, for the induction and maintenance of remission, respectively. The main limiting factors for the repeated use of corticosteroids or the use as a maintenance treatment are the very high prevalence of systemic side effects, together with the possibility of developing dependency on and/or resistance to the drug, which are reported in more than one third of patients with inflammatory bowel disease. In the last decade, a number of corticosteroids with enhanced topical activity and low systemic activity have been developed. Among them, budesonide and beclomethasone dipropionate are the most used for the treatment of the inflammatory bowel diseases. Indeed, budesonide is the drug of choice for the treatment of ileo(-cecal) active Crohn's disease with mild-to-moderate activity, due to controlled ileal release. Budesonide foam and/or enemas are also efficacious in the treatment of left-sided/distal ulcerative colitis. Gastro-resistant, extended release tablets characterized by a multimatrix structure (i.e. MMX-budesonide), have also been developed to allow uniform release along the length of the colon. This paper reviews the mechanism-of-action, safety and efficacy of budesonide in the treatment of inflammatory bowel disease.     

Review article: systemic and topical steroids in inflammatory bowel disease

Steroids are still widely used in the treatment of inflammatory bowel diseases. Pharmacological studies have shown that there is no major abnormality in the pharmacokinetics of steroids in these disorders. Foam preparations with rectal application decrease the bioavailability to low levels, eliminating systemic complications. For oral use, 'nonsystemic' steroids have been developed. In ulcerative colitis, steroids are rarely needed as 5-aminosalicylates are effective in the majority of patients. This is true for rectal application in distal colitis, as well as in more extensive disease. In Crohn's disease, steroids are more often used; however, in population-based studies, less than 50% of patients have been treated with steroids, as there are alternative treatments available for the large group of patients with mild to moderate activity. For those patients needing steroid treatment, budesonide seems to be a good choice in active disease, but has not shown convincing effects in the maintenance of remission over longer periods of time. There is no place for long-term steroid treatment in ulcerative colitis and very little in Crohn's disease--immunosuppression with azathioprine or related drugs is certainly the better alternative.     

Inflammatory bowel disease (ulcerative colitis and Crohn's disease): diagnostic criteria and differential diagnosis

Chronic inflammatory bowel diseases (i.e., ulcerative colitis and Crohn's disease) are syndromes in which standardized criteria are necessary in the diagnostic process. The present review is based on the diagnostic criteria used at our institution. We base the diagnosis of ulcerative colitis and Crohn's disease on combined information from the patient history, and radiological, endoscopic and histological findings after exclusion of neoplastic and infectious disease. The patient history must include precise information on the nature and duration of symptoms as well as the presence of relevant influential factors such as travel activity, drug intake and sexual habits. In immunocompromised patients extensive microbiological investigations are required to exclude infection. Typical radiological and colonoscopic findings in ulcerative colitis are mucosal inflammatory changes extending circumferentially and continuously from the rectum and proximally in the colon. In contrast, Crohn's disease is most frequently located in the small bowel and in case of colonic involvement, the rectum is often spared. The best predictors of Crohn's disease are discontinuous lesions, cobblestones and apthous ulceration. Histological changes such as abnormal mucosal architecture and lamina propria cellularity, neutrophil polymorph infiltration and epithelial cell abnormality are useful and reproducible features in the evaluation of colorectal biopsy specimens. The inflammatory bowel diseases, ulcerative colitis and Crohn's disease, continue to be etiological and diagnostic challenges. Increased use of standardized criteria and diagnostic algorithms are essential instruments to improve the overall quality of the management of patients with these diseases.     

The serum concentrations of zinc, copper and selenium in children with inflammatory bowel disease

OBJECTIVE: To estimate the levels of trace elements in children with inflammatory bowel disease (IBD). DESIGN: Prospective cross sectional study. SETTING: Gastroentrology Unit, Great Ormond Street Children's Hospital, London, UK. SUBJECTS: Seventy four children with inflammatory bowel disease confirmed endoscopically and histologically (38 ulcerative colitis and 36 Crohn's disease) and 40 age matched controls had their serum zinc, copper and selenium assayed at presentation. MAIN OUTCOME MEASURE: Serum levels of zinc, copper and selenium in children with inflammatory bowel disease and age matched controls. RESULTS: Seventy four children with inflammatory bowel disease confirmed endoscopically and histologically (38 ulcerative colitis and 36 Crohn's disease) and 40 age matched controls had their serum zinc, copper and selenium assayed at presentation. The serum levels of selenium were significantly lower in cases of ulcerative colitis 0.63 +/- 0.25 mmol/L and Crohn's disease 0.69 +/- 0.25 mmol/L than in the controls 0.84 +/- 0.13 mmol/L (p < 0.01). The serum copper concentration was significantly higher in those with Crohn's disease 22.7 +/- 5.49 mmol/L than in those with ulcerative colitis 17.6 +/- 5.15 mmol/L and the controls 20.76 +/- 4.06 mmol/L (p < 0.01). Children with Crohn's disease had a lower serum zinc level 11.01 +/- 2.49 mmol/L compared to the control level of 13.6 +/- 1.63 mmol/L (p < 0.05), but the levels were not significantly different in the controls and ulcerative colitis (p > 0.10). Children with inflammatory bowel disease have abnormal levels of the trace elements which is more marked in those with Crohn's disease. CONCLUSION: Children with IBD in this study show abnormalities of the trace elements which is probably a result of inadequate intake, reduced absorption, increased intestinal loss due to impairment of the absorption as a result of the inflammatory process. The reduced free radical scavenging action of zinc and selenium as a result of their deficiency may contribute to the continued inflammatory process of IBD. The recommendation of the supplementation of these trace elements in IBD is further supported by the findings of this study in children.     

The efficacy of methotrexate for maintaining remission in inflammatory bowel disease

BACKGROUND: The management of patients with inflammatory bowel disease who are resistant to or intolerant of azathioprine remains a challenge. Low-dose methotrexate has been shown to be effective in inducing remission in Crohn's disease. AIM: This review was conducted because there are limited long-term follow-up data during and after stopping treatment. There are also limited data on the use of methotrexate in ulcerative colitis. METHODS: The study was a retrospective review of clinical notes. Remission was defined as minimal bowel symptoms without the need for oral steroids for 3 months. Relapse was defined as bowel symptoms that required steroid treatment or surgery. RESULTS: Seventy patients were reviewed; 48 had Crohn's disease and 22 had ulcerative colitis. The mean duration of treatment was 17.1 months; the mean maintenance dose was 20 mg weekly. Remission was achieved in 34 of 55 patients who completed more than 3 months of treatment (62%). Life-table analysis showed that the chances of remaining in remission at 12, 24 and 36 months (if treatment was continued) were 90%, 73% and 51%, respectively. The chances of remaining in remission after stopping treatment at 6, 12 and 18 months were 42%, 21% and 16%, respectively. The dose of methotrexate (mg/kg) was associated with the induction of remission (P=0.02). Treatment was equally effective for Crohn's disease and ulcerative colitis. CONCLUSIONS: Maintenance methotrexate treatment gives acceptable remission rates for treatment periods up to 3 years. After stopping treatment, relapse is frequent and occurs early (usually within 1 year).     

Steady-state pharmacokinetics of enteric coated 5-amino-salicylic acid tablets in healthy volunteers and in patients with Crohn''s disease or ulcerative colitis

An Eudragit-L coated oral 5-aminosalicylic acid (5-ASA; mesalazine) product (Mesasal), has been formulated to deliver 5-ASA to the distal small bowel and colon for the treatment of inflammatory bowel disease. The purpose of this study was to compare the pharmacokinetic profile of this product at steady-state between healthy volunteers and two different patient groups with inflammation of either the small or the large bowel. Two carefully selected groups of patients, nine with Crohn's disease restricted to the small intestine and ten with total ulcerative colitis and one group of ten healthy volunteers received two 250 mg Mesasal tablets three times daily for 10 days to reach steady-state. Plasma 5-ASA and acetyl-5-ASA concentrations were followed for 48 h and urinary excretion for 72 h. There was a great variation in most pharmacokinetic parameters within each group and no significant differences were noticed between the groups. The location of the inflammatory process probably does not influence the pharmacokinetics of 5-ASA in any significant way in patients with either Crohn's disease in the small bowel or total ulcerative colitis.     

Review article: complementary and alternative therapies for inflammatory bowel disease

Complementary and alternative medicine includes a wide range of practices and therapies outside the realms of conventional western medicine. Despite a lack of scientific data in the form of controlled trials for either efficacy or safety of complementary and alternative medicine, use by patients with inflammatory bowel disease, particularly of herbal therapies, is widespread and increasing. There is limited controlled evidence indicating efficacy of traditional Chinese medicines, aloe vera gel, wheat grass juice, Boswellia serrata and bovine colostrum enemas in ulcerative colitis. Encouraging results have also been reported in small studies of acupuncture for Crohn's disease and ulcerative colitis. Contrary to popular belief, natural therapies are not necessarily safe: fatal hepatic and irreversible renal failure have occurred with some preparations and interactions with conventional drugs are potentially dangerous. There is a need for further controlled clinical trials of the potential efficacy of complementary and alternative approaches in inflammatory bowel disease, together with enhanced legislation to maximize their quality and safety.     

Review--antibiotic treatment in inflammatory bowel disease: rifaximin, a new possible approach

The etiology of inflammatory disease is still unknown, but a body of evidence from clinical and experimental observation indicates a role for intestinal microflora in the pathogenesis of this disease. Reduction of microflora using antibiotics, bowel rest and fecal diversion decreases activity in Crohn's disease and in ulcerative colitis. Several trials have been carried out on the use of antibiotic treatment in patients with active ulcerative colitis with contrasting results. A number of trials have been carried out using Rifaximin, a non-absorbable broad-spectrum antibiotic, confirming the absence of systemic bioavalaibility of the drug even when administered at very high doses and for prolonged periods. It may therefore be useful in treatment of ulcerative colitis and pouchitis, since its absorption through inflamed mucosa is negligible, it maintains a topical action without systemic effects and the lack of resistant bacterial strains may allow prolonged and repeated treatments.     

Oral beclomethasone dipropionate: a critical review of its use in the management of ulcerative colitis and Crohn's disease

Crohn's disease and ulcerative colitis are inflammatory bowel diseases characterised by a chronic relapsing course. Corticosteroids represent the mainstay of medical treatment of inflammatory bowel disease for the induction of remission. Despite the high efficacy of systemic steroids, their use is limited by the high incidence of potentially serious adverse effects. The topically acting steroids are synthetic compounds characterised by high anti-inflammatory activity and low systemic effects by virtue of efficient first-pass hepatic inactivation. Budesonide and Beclomethasone Dipropionate are the two most studied topically acting steroids in inflammatory bowel disease. Oral Budesonide has been extensively studied in the treatment of mild to moderate ileo-caecal Crohn's disease but few data are available concerning oral Beclomethasone Dipropionate. This review focuses on the available evidence of efficacy and safety of oral Beclomethasone Dipropionate in the management of ulcerative colitis and Crohn's disease and a possible role of this steroid in clinical practice is suggested.     

Review article: smoking cessation as primary therapy to modify the course of Crohn's disease

This article aims to offer an updated review of the effects of smoking on inflammatory bowel disease, and provide a review of the methods of achieving smoking cessation. A systematic review of Embase and Medline databases was conducted. Smoking causes opposing effects on ulcerative colitis and Crohn's disease. The odds ratio of developing ulcerative colitis for smokers compared with lifetime non-smokers is 0.41. Conversely, smokers with Crohn's disease have a more aggressive disease requiring more therapeutic intervention. Smoking cessation is associated with a 65% reduction in the risk of a relapse as compared with continued smokers, a similar magnitude to that obtained with immunosuppressive therapy. Although difficult to achieve smoking cessation can best be encouraged by accessing appropriate counselling services, nicotine replacement therapy and bupropion. Using a combination of these treatments there is an improved chance of success of up to 20% compared with an unassisted quit attempt. Smoking cessation unequivocally improves the course of Crohn's disease and should be a primary therapeutic aim in smokers with Crohn's disease.     

Therapeutic inhibitors of tumor necrosis factor in Crohn's disease

Therapeutic options for patients with refractory ulcerative colitis or Crohn's disease have recently been augmented by the introduction of biological therapies. The pro-inflammatory cytokine, tumor necrosis factor (TNF)-alpha is present in elevated concentrations in patients with inflammatory bowel disease and inhibitors of TNF alpha have proved effective as treatment. Strategies aimed at reducing TNF in patients with Crohn's disease, include the mouse/human chimeric monoclonal antibody, infliximab (Centocor Inc), the humanized monoclonal antibody, CDP-571 (Celltech Group plc), the human recombinant TNF receptor fusion protein, etanercept (Immunex Corp), and thalidomide. New approaches, including the use of soluble TNF receptors, appear promising. This article reviews the evidence of therapeutic inhibition of TNF.     

The association of MYO9B gene in Italian patients with inflammatory bowel diseases

Background  Variants of myosin IXB ( MYO9B ) gene, encoding for a motor protein implicated in epithelial permeability, have been recently associated with inflammatory bowel disease.
Aims  To investigate the contribution of three polymorphisms of MYO9B gene for predisposition to Crohn's disease and ulcerative colitis, their association with clinical phenotypes, particularly intestinal permeability, and possible interaction with the CARD15 gene.
Methods  549 Crohn's disease patients, 658 ulcerative colitis patients and 674 controls were genotyped for the rs962917, rs1545620 and rs2305764 single nucleotide polymorphisms.
Results  Highly significant genotypic association with Crohn's disease and ulcerative colitis was shown for all three single nucleotide polymorphisms, with odds ratio ranging from 1.5 to 1.7 ( P -value: <0.01 to <0.002). A significant difference in allele frequencies was also observed in inflammatory bowel disease patients, with the single most significant association for rs1545620, detected in 47% of Crohn's disease, 47% of ulcerative colitis patients and 42% of controls ( P  < 0.005). No association with specific sub-phenotypes was found, with the exception of a trend towards an abnormal intestinal permeability ( P  = 0.043) in Crohn's disease carrying the rs1545620 risk allele.
Conclusions  Our findings confirm the association between the MYO9B polymorphisms and susceptibility to both ulcerative colitis and Crohn's disease, with a weak influence on sub-phenotypic expression.