Role of mesalazine in acute and long-term treatment of ulcerative colitis and its complications

BACKGROUND: Sulfasalazine, consisting of 5-aminosalicylic acid bound to sulfapyridine by a diazo bond, was first used for treatment of ulcerative colitis in the early 1940s and later found effective in placebo-controlled trials for acute disease and for long-term maintenance of remission. Later studies found that the active moiety is 5-ASA (mesalazine, mesalamine) and the sulfapyridine moiety acts as a carrier molecule but causes many of the symptomatic adverse reactions. METHODS: Review of the literature. RESULTS: The finding that 5-ASA in the active motility led to the development of mesalazine prodrugs, olsalazine (Dipentum) and balsalazide (Colazide, Colazal), and targeted release mesalazine preparations, such as Asacol, Pentasa, and Salofalk, as well as enemas and suppository preparations for distal disease. Most patients with adverse effects from sulfasalazine will tolerate mesalazine. Mesalazine has been shown equivalent or superior to sulfasalazine, and superior to placebo, with a dose-response benefit, in inducing remission of acute disease. and comparable to sulfasalazine and superior to placebo for long-term maintenance of remission. Better tolerance of mesalazine and the ability to use higher doses favor its use in patients intolerant of sulfasalazine and in patients failing to respond to usual doses of sulfasalazine. Adverse effects from mesalazine are uncommon, but include idiosyncratic worsening of the colitis symptoms and renal toxicity. Mesalazine is safe to use during pregnancy and for nursing mothers. As maintenance therapy, mesalazine may reduce the risk of developing colorectal carcinoma. CONCLUSION: Mesalazine represents effective and well-tolerated first-line therapy for mildly to moderately acute disease as well as for the long-term maintenance treatment in the patient with ulcerative colitis.     

Putting rectal 5-aminosalicylic acid in its place: the role in distal ulcerative colitis

Oral aminosalicylates such as sulfasalazine and mesalamine are widely prescribed for the treatment of mild or moderately active distal ulcerative colitis. However, a critical review of the literature demonstrates that rectal 5-aminosalicylic acid (5-ASA) is the optimal therapy for this disease. Meta-analyses of published trials show that rectally delivered 5-ASA is superior to placebo and to conventional rectal corticosteroids in inducing remission of distal ulcerative colitis, whereas the combination of rectal 5-ASA with a rectal corticosteroid or oral aminosalicylate is superior to rectal 5-ASA alone. For maintaining remission of distal ulcerative colitis, rectal 5-ASA is significantly better than placebo and at least as effective as oral 5-ASA. The dosage forms available for rectal delivery include suppositories, foams, and liquid enemas, and selection among these preparations should be guided by the proximal extent of disease and patient preference. The efficacy of rectal 5-ASA is complemented by its low rate of reported adverse effects, which may reflect its reduced potential for systemic absorption. This review summarizes the evidence supporting the role of rectal 5-ASA as a first-line therapy for mild or moderately active distal ulcerative colitis, and offers guidelines for its use.     

Topical therapy is underused in patients with ulcerative colitis

The availability of new topical preparations for the treatment of left sided ulcerative colitis offers a therapy optimization for many patients. Rectal application of steroids and 5-aminosalicylic acid (5-ASA) is associated with fewer side effects and has a higher therapeutic efficacy in left-sided colitis as compared to a systemic therapy. Therefore, we were interested in the use of topical therapy in patients with ulcerative colitis. The key question was whether topical treatment is more frequently used than oral therapy in patients with proctitis and left sided colitis. Data of 800 patients of the Swiss IBD cohort study were analyzed.Sixteen percent of patients of the cohort had proctitis, 21% proctosigmoiditis and 41% pancolitis. Topical therapy with 5-ASA or corticosteroids was given in 26% of patients with proctitis, a combined systemic and topical treatment was given in 13%, whereas systemic treatment with 5-ASA without topical treatment was given in 29%. Proportion of topical drug use decreased with respect to disease extension from 39% for proctitis to 13.1% for pancolitis (P = 0.001). Patients with severe colitis received a significantly higher dose of topical 5-ASA than patients in remission.Side effects of topical or systemic 5-ASA or budesonide treatment were less frequently seen compared to other medications. Topical treatment was frequently stopped over time. The quality of life was the same in patients with limited disease compared to patients with pancolitis.Topical treatment in proctitis patients was underused in Switzerland. Since topical treatment is safe and effective it should be used to a larger extend.     

Disposition of 5-aminosalicylic acid by olsalazine and three mesalazine preparations in patients with ulcerative colitis: comparison of intraluminal colonic concentrations, serum values, and urinary excretion.

To compare the disposition of 5-aminosalicylic acid (5-ASA) and its acetylated metabolite during treatment with olsalazine and mesalazine, 14 patients with inactive ulcerative colitis were randomly assigned to olsalazine (1 g twice daily) and the mesalazines, Asacol (800 + 400 + 800 mg daily), Pentasa (750 + 500 + 750 mg daily), and Salofalk (750 + 500 + 750 mg daily) in a crossover design trial so that all received each drug for seven days. Intraluminal colonic concentrations of 5-ASA were estimated after five days by the method of equilibrium in vivo dialysis of faeces. A predose serum sample and a 24 hour urine collection were obtained on day seven. The 5-ASA and acetyl-5-aminosalicylic acid (Ac-5-ASA) values were determined by high performance liquid chromatography. Olsalazine almost doubled the colonic concentrations (mean 23.7 (SEM) (1.9) mmol/l) of its therapeutically active ingredient (5-ASA) compared with equimolar doses of Pentasa (12.6 (2.2) mmol/l; p less than 0.0003) and Salofalk (15.0 (2.0) mmol/l; p less than 0.003). At the same time, olsalazine treatment was associated with lower serum concentrations and urinary excretions (p less than 0.05) of 5-ASA and Ac-5-ASA compared with the mesalazine preparations. The low systemic load of 5-ASA provided by olsalazine reduces the potential risk of nephrotoxicity during long term treatment.     

Oral 4-aminosalicylic acid versus 5-aminosalicylic acid slow release tablets. Double blind, controlled pilot study in the maintenance treatment of Crohn's ileocolitis.

4-Aminosalicylic acid (4-ASA) has been suggested as an effective treatment for both active and quiescent ulcerative colitis. 5-Aminosalicylic acid (5-ASA) is well accepted for the maintenance treatment of inactive ulcerative colitis. Moreover, recent studies suggest that 5-ASA may also be effective in maintaining remission in Crohn's colitis. As treatment with 4-ASA may result in less side effects, the efficacy of a one year's maintenance treatment with oral 4-ASA (1.5 g/d, slow release tablets, n = 19) and oral 5-ASA (1.5 g/d, slow release tablets, n = 21) was compared in a double blind, randomised trial in patients with quiescent Crohn's ileocolitis. Patients with ileocolonic or colonic involvement were enrolled if in stable remission for more than two months but less than one year. Baseline demography and clinical severity were similar in both groups. Total colonoscopy and ileoscopy were performed at enrollment and at the end of the study. After one year seven of 19 patients receiving 4-ASA (36%) and 8 of 21 receiving 5-ASA (38%) had developed a clinical relapse, as defined by a rise in the Crohn's disease activity index (CDAI) of more than 100 points to values higher than 150. The relapse rates between the 4-ASA and the 5-ASA groups were not statistically different although no comparison with the spontaneous relapse rate in a placebo group could be made. Clinical relapse was accompanied by a statistically significant rise in serum concentrations of soluble interleukin 2 receptor and by an increased percentage of activated peripheral blood T cells. There were no statistical differences between the 4-ASA and the 5-ASA groups regarding the height of rise in CDAI or of soluble interleukin 2 receptor concentrations during relapse, thus showing a similar severity relapsed disease activity. In conclusion, 4-ASA maybe as effective as 5-ASA in the maintenance treatment of quiescent Crohn's disease and there were no differences in the severity of relapse between both treatment groups.     

Optimum dosage of 5-aminosalicylic acid as rectal enemas in patients with active ulcerative colitis.

5-Aminosalicylic acid (5-ASA), the active moiety of sulphasalazine (SASP), was given as a rectal enema to patients with mild to moderate distal ulcerative colitis to determine the minimum effective dosage. A double blind study was carried out using enemas containing 1, 2, or 4 g or 5-ASA or placebo for a one month treatment period. One hundred and thirteen patients with ulcerative colitis attending our outpatient clinic volunteered to participate. Clinical, sigmoidoscopic, and histological assessments were carried out at the beginning of the study and after 15 and 30 days of treatment. All patients who received 5-ASA enemas showed significantly better results than those who received a placebo enema (p less than 0.001) but no difference was detected among the patients receiving differing concentrations of 5-ASA. This study suggests that 1 g 5-ASA (in a 100 ml enema) is a sufficient dosage for patients with a mild to moderate attack of ulcerative colitis.     

Expert opinion:Experience with 6-mercaptopurine in the treatment of inflammatory bowel disease

Arbitrarily, modern day treatment of inflammatory bowel disease begins with the introduction of immuno- suppressives for ulcerative colitis. Clinical improvement with sulfasalazine had been meaningful but modest. Treatment with adrenocorticotropic hormone and corti- costeroids led to clinical responses never before realized but it took much too long to recognize that they were not capable of maintaining remission, that adverse reactions were subtle but potentially devastating and that some other agent would be necessary to capitalize on their transient advantage. This of course was true in the treatment of Crohn’s disease as well. Not much was ever made of the role of sulfasalazine for Crohn’ s disease, but with the severing of the diazobond and the elimination of the sulphur component, the 5-ami- nosalacylic acid (5-ASA) products clearly led to clinical improvement, especially in cases of Crohn’s colitis and those with ileitis where the 5-ASA product was released in the terminal ileum and more proximal in the small bowel as well as in ulcerative colitis. The induction of remission was first demonstrated by 6-mercaptopurine (6-MP) with case reports and uncontrolled trials in pa- tients with ulcerative colitis, but its placebo controlled trial for Crohn’s disease firmly established its role in inducing remission. No subsequent trial has confirmed its similar role for ulcerative colitis, but nevertheless cli- nicians know well that 6-MP works at least as well and probably more effectively for ulcerative colitis than for Crohn’s disease. What changes have taken place utiliz- ing 6-MP in the management of inflammatory bowel disease since its introduction in the 1960’s and 1970’s and its trial for Crohn’s disease published in the New England Journal of Medicine in 1980?     

Salicylates for inflammatory bowel disease

Targeted delivery of 5-aminosalicylic acid to the small intestine and colon by controlled-release or azo-bonded compounds potentially offers treatment for ileal Crohn's disease as well as ulcerative colitis. The pharmacokinetics of sulphasalazine and aminosalicylate derivatives have been discussed and potential modes of action reviewed. These include actions on epithelial cell-surface receptors, cellular events and barrier function. Evidence for an influence of salicylates on circulating and tissue inflammatory cells is presented, as well as actions on adhesion molecules, chemotactic peptides, eicosanoids, cytokines and reactive oxygen metabolites. The precise mechanism remains unknown, but a pluripotential mode of action is an advantage when influencing the network of events that constitutes chronic inflammation. Controlled clinical trials of salicylates in ulcerative colitis and Crohn's disease have been reviewed. Their main role remains as maintenance therapy for ulcerative colitis, but relatively high doses of controlled-release preparations benefit patients with ileal Crohn's disease, following resection, or those who have recently relapsed. Finally, issues of clinical relevance have been addressed, including the choice of salicylate and safety, indications for initiating therapy, dose and duration of treatment, role in managing refractory colitis and future developments.     

Incidence of inflammatory bowel disease in northern France (1988-1990).

There were no data concerning the incidence of inflammatory bowel disease (IBD) in France. The aim of this study was to investigate the incidence of Crohn''s disease and ulcerative colitis in northern France. This prospective population based study was realised through the gastroenterologists of the region Nord-Pas de Calais and the Somme Department. Each gastroenterologist referred patients consulting for the first time with clinical symptoms compatible with IBD. Data were collected by an interviewer practitioner present at the gastroenterologist''s consulting room. Two independent expert gastroenterologists assessed each case in a blind manner and made a final diagnosis of Crohn''s disease, ulcerative colitis, ulcerative proctitis, or unclassifiable chronic colitis. From 1988 to 1990, 1291 cases of IBD were recorded: 674 (52%) Crohn''s disease, 466 (36%) ulcerative colitis including 162 proctitis (35%), and 151 (12%) unclassifiable chronic colitis. The mean annual incidence was 4.9 per 100,000 for Crohn''s disease and 3.2 for ulcerative colitis. The sex ratio F/M was 1.3 for Crohn''s disease and 0.8 for ulcerative colitis. The highest age specific incidence rate for Crohn''s disease was between 20 and 29 years: 13.1 for women and 9.8 for men. The highest age specific incidence rate for ulcerative colitis was between 20 and 39 years: 5.5 for women and 6.5 for men. This first French prospective study has shown an incidence rate for Crohn''s disease comparable with that seen in north European studies but lower than that seen for ulcerative colitis. These results could be related to the different environmental factors or the genetic background of the population studied, or both.     

Family history of inflammatory bowel disease among patients with ulcerative colitis: A systematic review and meta-analysis

Background and aimsDespite numerous shared susceptibility loci between Crohn's disease and ulcerative colitis, the prevalence of family history among ulcerative colitis patients is not well-established and considered to be less prevalent. A systemic review and meta-analysis were conducted to estimate the prevalence of family history of inflammatory bowel disease in ulcerative colitis patients, and its effect on disease outcomes.MethodsPubMED was searched to identify studies reporting the prevalence of family history of inflammatory bowel disease among ulcerative colitis patients. Definitions of family history, study type, and subtypes of family history prevalence were abstracted, as were disease outcomes including age at ulcerative colitis diagnosis, disease location, surgery and extraintestinal manifestations. Pooled prevalence estimates were calculated using random effects models.ResultsSeventy-one studies (86,824 patients) were included. The prevalence of a family history of inflammatory bowel disease in ulcerative colitis patients was 12% (95% confidence interval [CI] 11 to 13%; range 0–39%). Family history of ulcerative colitis (9%; 22 studies) was more prevalent than Crohn's disease (2%; 18 studies). Patients younger than 18 years of age at time of diagnosis had a greater family history of inflammatory bowel disease (prevalence 15%, 95% CI: 11–20%; 13 studies). There were no differences in disease location, need for surgery, or extraintestinal manifestations among those with a family history, although very few studies reported on these outcomes.ConclusionsOverall, 12% of ulcerative colitis patients have a family history of inflammatory bowel disease, and were more likely to have a family history of ulcerative colitis than Crohn's disease. Pediatric-onset ulcerative colitis patients were more likely to have a family history of inflammatory bowel disease.     

Medical management of ulcerative proctitis, proctosigmoiditis, and left-sided colitis.

Ulcerative colitis distal to the splenic flexure includes disease confined to the rectum (proctitis), rectosigmoid (proctosigmoiditis or distal colitis), or extending to the descending colon or splenic flexure (left-sided colitis). These subtypes represent up to 60% to 80% of newly presenting cases of ulcerative colitis. Although these conditions are defined by the extent of colon that is affected, they also share the characteristic of being amenable to topical therapy. In general, the course of disease is milder and symptoms are less severe than in patients with more extensive colonic involvement. Nonetheless, symptoms may significantly impair patients' health-related quality of life. Treatment options include the oral and/or rectal 5-aminosalicylate (5-ASA) preparations. Rectal therapy delivering higher concentrations of active medication (5-ASA or glucocorticoids) directly to the inflamed mucosa while minimizing systemic absorption provides a highly effective and safe treatment. Oral glucocorticoids are indicated in patients who are resistant to or intolerant of 5-ASA therapy. Immunomodulators have an important role in individuals with glucocorticoid dependent or glucocorticoid refractory disease. This article reviews the clinical diagnosis and current medical management of ulcerative proctitis, proctosigmoiditis, and left-sided ulcerative colitis, including patients resistant to conventional medical therapy.     

Familial occurrence and inheritance studies in inflammatory bowel disease

A number of studies have demonstrated aggregation of cases of ulcerative colitis or Crohn's disease in families, and of cases of both diseases within the same families, suggesting that patients share a genetic background. Perhaps because of differences in the selection of patients, study design and diagnostic criteria, different patterns of occurrence of inflammatory bowel disease (IBD) have been found among relatives of patients with these disorders. In recent years, however, several studies have been carried out, aiming by epidemiological methods to reveal (1) the frequency of familial occurrence of IBD among patients with ulcerative colitis and Crohn's disease, and (2) the prevalence of IBD among 1⁰ relatives to patients with these diseases. Results from these studies show a relatively uniform pattern of family occurrence in about 10% of patients with ulcerative colitis and Crohn's disease, and a prevalence among 1⁰ relatives of about 10 times that of the background population. A twin study reported a significantly higher concordance rate for Crohn's disease than for ulcerative colitis in monozygotic twins. By use of complex segregation analyses in 3 different studies, a very similar model of inheritance was found to fit for ulcerative colitis, namely a major dominant or additive gene with a low penetrance. For Crohn's disease the best-fitting model was a major recessive gene, with a high penetrance. This difference strongly supports the concept of ulcerative colitis and Crohn's disease as two separate disease entities. The occurrence of both diseases within the same families in certain members of the affected families is difficult to explain. The search for distinct associations of HLA genes with inflammatory bowel disease has shown a positive correlation between DR2 and ulcerative colitis and a negative association with DR4 and DRw6, compared with ethnically matched controls. In contrast, in Crohn's disease a positive association with the combination of DR1 and DQw5 alleles was revealed, thus indicating genetically different disease susceptibility for the two disorders. In general, however, no consistent pattern has been revealed from studies of association of HLA-A or -B antigens or blood group and serum protein markers. In two French families with several members affected with Crohn's disease no evidence for an HLA haplotype association could be revealed. Possible inherited markers of ulcerative colitis or Crohn's disease have been sought but without convincing success. Increased intestinal permeability, presence of anticolon antibodies and presence of antineutrophil leukocyte antibodies have been proposed, but not proved. Thorough studies are now needed of multimember families with disease for linkage studies to identify loci which contribute to increased liability. Such studies are in progress in different centres.     

Ulcerative colitis therapy: importance of delivery mechanisms

Since the initial observation that mesalamine or 5-aminosalicylate (5-ASA) has an anti-inflammatory effect on ulcerative colitis, investigators have been trying to improve on the delivery mechanisms of this compound. As it is believed that the anti-inflammatory effect of 5-ASAs is mediated topically, current formulations are designed to release 5-ASA in the small intestine and colon, or predominantly in the colon. A dose-response curve is seen with some preparations of mesalamine but not all. In general, 5-ASAs are effective in patients with ulcerative colitis and much less effective in Crohn's disease. Evidence demonstrates that 5-ASAs are effective for induction of remission and maintenance of remission. Preparations that deliver 5-ASA in a pH-dependent manner are most affected by variability in luminal pH, whereas those that depend on bacterial cleavage for release of the active 5-ASA are most affected by transit time. Most studies have not compared different preparations of mesalamine and examined differences in colonic delivery. Depending on the endpoint examined in the studies, efficacy of the various 5-ASA products appears similar at the most optimal doses. For a given patient, however, it may be necessary to experiment with more than one preparation if an initial trial results in a suboptimal response.     

Smoking Habits in Patients with Inflammatory Bowel Disease

The proportion of smokers in this study was significantly lower among patients with ulcerative colitis (13%) than among patients with Crohn's disease (47%), the difference being significant for both sexes and for the age groups both below and above 40 years. The proportion of male ex-smokers among patients with ulcerative colitis (28%) was higher than among patients with Crohn's disease (8%), whereas the proportions of non-smokers differed less. Many of the patients with ulcerative colitis who had a late onset were male ex-smokers. The smoking patients with ulcerative colitis were mainly women. They smoked less than the smoking patients with Crohn's disease and less than the ex-smokers in each group. No smoking patient with ulcerative colitis smoked > 20 cigarettes/day. In the group of male ex-smokers with ulcerative colitis, there was an accumulation of onsets during the 4 years after the definitive smoking stop. The number of colectomies performed on patients with ulcerative colitis did not vary with smoking habits. In the group of ex-smokers the colectomy was performed after the smoking stop in 19 out of 20 patients.     

Adherence of gastroenterologists to European Crohn's and Colitis Organisation consensus on ulcerative colitis: A real-life survey in Spain

Background & aimsA European consensus on the management of ulcerative colitis (UC) was recently published; however, there is no adequate evidence about adherence to such guidelines among gastroenterologists. This knowledge would allow the local evaluation of the situation and the adoption of actions to reduce the existent clinical variability.MethodsA cross-sectional survey was conducted in Spain to assess the adherence to the European Crohn's and Colitis Organisation (ECCO) guidelines on mild to moderate UC. We surveyed 700 gastroenterologists, and finally a total of 530 gastroenterologists specialised in inflammatory bowel disease (GSIBDs) and general gastroenterologists (GGs), responded to the survey (76%).ResultsAgreement with the guidelines was high; discrepancies included that only 25% of the GGs used the combination of oral and topical 5-aminosalycilic acid (5-ASA) for treating extensive UC vs 45% of the GISBDs. In addition, topical rectal steroids were considered as effective as topical mesalazine by 48% of the GGs vs 31% of the GSIBDs, indefinite treatment with 5-ASA was prescribed by only 26% of the GGs vs 41% of the GSIBDs, and the once daily dosing of 5-ASA was generally used by 46% of the GGs vs 51% of the GSIBDs.ConclusionsThe questionnaire showed a high degree of agreement between GGs and GSIBDs. Nevertheless, the GSIBD group showed closer agreement with the ECCO guidelines. Furthermore, some shortcomings were found in the GG group, in which increased maintenance treatment with 5-ASA, the use of a single daily dose of 5-ASA, and the use of combined oral and topical treatment for distal colitis should be advised.     

4-Aminosalicylic acid retention enemas in treatment of distal colitis

Forty-five of 47 patients with distal ulcerative colitis completed a two-week double-blind, randomized, controlled trial to determine if 4-aminosalicylic acid (4-ASA) enemas, 1 g bid or 2 g bid, were therapeutically effective compared to placebo. Forty-one patients enrolled because they were refractory to or had side effects during conventional therapy with sulfasalazine or corticosteroids. Proctoscopic examination was done before and after two weeks of treatment. Patients kept daily diaries assessing: (1) blood in stools, (2) mucus in stools, (3) tenesmus, (4) abdominal pain, (5) loss of appetite, (6) fatigue, (7) weight loss, and (8) malaise. Severity of each symptom ranged from 0 (absent) to 3 (severe). A total severity score was calculated from the above for each patient. At the end of the two-week study, 35 patients elected to take 4-ASA in an open-label trial for one year. 4-ASA enemas in the 1-g bid but not the 2-g bid dosage were significantly more effective in improving symptoms than placebo:P<-0.05. Neither dose of 4-ASA enema was better than placebo in improving the sigmoidoscopic appearance at the end of two-weeks. Forty-six percent of patients had complete resolution of all signs and symptoms in the open-label trial and 31% were better but still had sigmoidoscopic evidence of disease, a total response rate of 77%. Side effects were similar in the placebo and 4-ASA groups. We conclude that 4-ASA enemas in a dose of 1 g bid are safe and effective in the treatment of distal ulcerative colitis.Supported in part by Research Training Grant AM 07024 from the National Institutes of Health     

Controlled Trial of 4-ASA in Ulcerative Colitis

A six-week placebo-controlled trial of theefficacy and safety of 6 g per day of 4-aminosalicylicacid (4-ASA) was conducted in 30 subjects with mild tomoderately severe ulcerative colitis. Subjects were stratified into groups having distal (<60cm) or more extensive (>60 cm) disease. Diarrhea,bleeding, sigmoidoscopic and biopsy appearance, andphysician global assessment were scored to judgeefficacy. Safety was evaluated by monitoring untowardsymptoms and laboratory values. Median percentimprovement was significantly greater (P < 0.05) inthe 4-ASA 60-cm group (42.7%) than in the placebo 60-cmgroup (21.2%), but 4-ASA was not better than placebofor the 60-cm group or the total study group. Severedyspepsia (one subject), abnormal AST (transient infive, persistent in one) and elevated lipase without pancreatitis (six subjects) were noted. Thus 6g 4-ASA for six weeks was more effective than placebo inmild to moderate ulcerative colitis extending more than60 cm above the anus, but not in distal disease, and the drug was generally welltolerated.     

5-Aminosalicylic acid enemas in treatment of distal ulcerative colitis and proctitis in Canada

The efficacy and safety of 4 g 5-aminosalicylic acid (5-ASA) enemas were assessed in 59 patients with ulcerative colitis involving up to 50 cm of their distal colon. Twenty-nine patients received 5-ASA and 30 received a placebo. There were 12 dropouts (five in the active and seven in the placebo group) during the study because of insufficient efficacy. After six weeks of therapy, 63% of the patients receiving the 5-ASA were considered to be “much improved” by the study physician compared to 20% patients on placebo (P<0.0001). A disease activity index (DAI), based upon patient symptoms and sigmoidoscopic appearance, was used to assess efficacy. Mean DAI declined 75% for patients on 5-ASA enemas and 32% for patients on placebo (P<0.05). The 5-ASA enemas are well tolerated and are of benefit in the treatment of ulcerative colitis confined to the distal colon.     

Therapeutic efficacy of 5-ASA molecules in idiopathic intestinal inflammatory diseases: critical review]

Sulfasalazine has been the most widely prescribed drug for patients with inflammatory bowel disease. Clinical trials have established its usefulness in treating patients with active ulcerative colitis and Crohn colitis and its important role in maintaining remissions in patients with ulcerative colitis. Despite its widespread acceptance, the usefulness of sulfasalazine has been limited by the occurrence of adverse reactions in about 10 to 20% of the patients. Now the aminosalicylates are emerging as a treatment for both ulcerative colitis and Crohn disease. We have critically reviewed the clinical trials assessing the efficacy of 5-ASA molecules. Therapeutic efficacy of 5-ASA appears to be as good as sulfasalazine but causing less adverse effects. In mild to moderate ulcerative colitis relapse, 2g 5-ASA is active while 1 g 5-ASA seems equivalent to 2g sulfasalazine for maintaining remission. 5-ASA enema in the treatment of distal ulcerative colitis is helpful and can replace topical cortisone administration. Administration of 1g 5-ASA enema a day seems to be the best regimen. In case of Crohn's disease, preliminary studies are encouraging but more date are required to define the indications as well as the regimen.     

Refractory IBD: medical management

Refractory inflammatory bowel disease (IBD) can be defined as persistent acute symptomatic disease despite anti-inflammatory therapy or as chronically active disease requiring continuous treatment for relief of symptoms. Treatment options include azathioprine (AZA), 6-mercaptopurine (6-MP), methotrexate (MTX), cyclosporine (CYA), and experimental therapies that are cytokines or cytokine antagonists. AZA and 6-MP have identical actions in IBD. 6-MP is effective in about 75% of patients with inflammatory Crohn's disease. The mean time until the onset of action is 3.1 months. AZA is effective in ulcerative colitis as a steroid-sparing agent. Side-effects occur in 10–15% of patients on AZA or 6-MP for IBD. MTX induces symptomatic remission in about 40% of patients with Crohn's disease. The potential for hepatic fibrosis from MTX is a concern. CYA appears effective in the acute management of severe ulcerative colitis. CYA has not proven useful in the long-term management of Crohn's disease. Potentially serious side-effects include hypertension and renal insufficiency. The cytokine antagonist, anti-tumor-necrosis-factor-alpha antibody, and the anti-inflammatory cytokine, interleukin 10, appear promising for the treatment of Crohn's disease.