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Objectives: A multicenter double-blind placebo-controlled clinical study was conducted to evaluate the efficacy and tolerability of two different therapeutic schedules of mesalazine suppositories in patients with ulcerative proctitis. Methods: From 1990 to 1993, 111 patients with ulcerative proctisis in remission, limited to the rectum (≤ 15 cm from anus), were enrolled. After obtaining informed consent, patients were randomized to three treatment groups: 500 mg mesalazine b.i.d. (36 patients), 500 mg mesalazine u.i.d. (40 patients), and placebo (35 patients). The treatment lasted 1 yr. Follow-up consisted of periodic clinical, endoscopic, and histological assessments. An endoscopic score > 1 according to the Baron scale defined relapse occurence. The three groups were homogeneous as regards main demographic, diagnostic, and prognostic features. Results: The cumulative relapse rates at 12 months were 10% (95% confidence interval [CI]: 0–21) in the mesalazine b.i.d. group, 32% (95% CI: 16–49) in the mesalazine u.i.d. group, and 47% (95% CI: 29–65) in the placebo group. The comparison between the mesalazine b.i.d. group and the mesalazine u.i.d. group cumulative relapse rates gave a p value of 0.0334, whereas the corresponding comparison between the mesalazine b.i.d. group and the placebo group gave a p value of 0.007 (log-rank test). The dose-response relationship was statistically significant (p = 0.008 by Cox analysis). Two patients in the mesalazine b.i.d. group, two patients in the mesalazine u.i.d. group, and one patient in the placebo group withdrew from the study due to nonserious adverse events; four, three, and four patients per group, respectively, dropped out because of poor compliance. Two patients in the mesalazine u.i.d. group and two in the placebo group were lost to follow-up. Conclusions: The results of this study confirm the therapeutic efficacy of mesalazine suppositories in the maintenance treatment of ulcerative proctitis. According to our experience the most effective therapeutic schedule is 500 mg mesalazine b.i.d.

BACKGROUND: Erosive reflux disease (ERD) and non-erosive reflux disease (NERD) are often regarded as part of the spectrum of the same disease. AIM: To elucidate molecular features that characterise NERD and ERD at the protein level. METHODS: A total of 56 consecutive subjects were enrolled: 10 healthy subjects, 24 with NERD and 22 with ERD. Eight specimens were taken from macroscopically normal mucosa at 5 cm of gastro-oesophageal junction. Four were processed for the proteins extraction and four for evaluation using haematoxylin-eosin and immunohistochemistry. We used shotgun proteomics to identify tentative disease molecular features for ERD or NERD. Candidate distinctive proteins were verified using immunohistochemistry. RESULTS: Shotgun proteomics analysis revealed 33 differentially expressed proteins in NERD vs. ERD samples, involved in cellular proliferation, keratinisation, stress responses and sugar metabolism. Based on a gene ontology meta-analysis, seven of them were further analysed using Western blotting (WB) and four also using immunohistochemistry. We identified novel candidate disease molecular features for GERD and few distinctive proteins to discriminate NERD and ERD. In particular, Transitional Endoplasmic Reticulum ATPase (TER ATPase), GAPDH, Alpha 1 Acid Glycoprotein 1, Annexin A1, Calmodulin and 14-3-3 proteins were confirmed at WB analysis. CONCLUSIONS: Non-erosive reflux disease and ERD are distinct disease entities at the protein level. This study proposes an array of candidate biomarkers possibly useful to discriminate between NERD and ERD.

Chronic refractory pouchitis is a long-term complication after ileal pouch-anal anastomosis and it may be associated with ileal inflammation.To determine the efficacy of infliximab in treatment of chronic refractory pouchitis complicated by ileitis, using a wireless capsule endoscopy.Sixteen patients with chronic refractory pouchitis complicated by ileitis were enrolled. Pouchitis was diagnosed by clinical, endoscopic and histological criteria. Ileitis was documented using wireless capsule endoscopy. Duodenum-jejunum and proximal-middle ileum were evaluated and the presence of small lesions and large lesions were noted. Crohn's disease, intestinal infections were excluded in all patients. Patients were treated with infliximab and clinical response was recorded. Wireless capsule endoscopy was repeated at week 10 and Pouchitis Disease Activity Index score was determined.Ten patients were enrolled and completed the study. Clinical remission was achieved in nine patients. At wireless capsule endoscopy and pouch endoscopy, a complete recovery of lesions was observed in eight patients. One patient presented four small lesions of the ileum at the 6 weeks of treatment and one patient did not show any modification. Clinical and endoscopic remission was maintained in these eight patients at least 6 months.These preliminary results indicate that infliximab may be recommended for the treatment of chronic refractory pouchitis complicated by ileitis.

Pouchitis is a common long-term complication after ileal pouch anal anastomosis for ulcerative colitis. Chronic refractory pouchitis is a treatment-resistant condition that affects 5-15% of patients.To test the hypothesis of a small bowel involvement using wireless capsule endoscopy.This is a single-blind, prospective, cohort study. Twenty-four patients: 16 were patients with chronic refractory pouchitis and eight, with a macroscopically and histologically normal ileal pouch, were considered as control subjects. Diagnosis of pouchitis was confirmed using the pouchitis disease activity index. All subjects were submitted to wireless capsule endoscopy procedure. Within 2 weeks before wireless capsule endoscopy, patients underwent a pouch endoscopy and a small bowel follow-through. Re-examination of the colonic surgical and histological specimens was also performed.One patient with chronic pouchitis was excluded because of incomplete bowel cleaning. At small bowel follow-through of 16 patients, two subjects (13%) showed only a focal ectasia of the middle ileum and a substenosis of the pouch. At wireless capsule endoscopy all the 15 evaluable patients with chronic pouchitis (100%) showed diffuse lesions from duodenum to ileum consisting of aphthae, erosions, erythema, atrophy, cobblestone, deep/fissural ulcers.This enteropathy needs further research, and wireless capsule endoscopy could be useful to show involvement of small bowel in patients with chronic pouchitis.

Pouchitis is the major long-term complication after ileal-pouch nal anastomosis for ulcerative colitis. Ten to 15% of patients develop a chronic pouchitis, either treatment responsive or treatment refractory.To evaluate the efficacy of oral budesonide in inducing remission and improving quality of life in patients with chronic refractory pouchitis.Twenty consecutive patients with active pouchitis, not responding after 1 month of antibiotic treatment were treated with budesonide controlled ileal release 9 mg/day for 8 weeks. Symptomatic, endoscopic and histological evaluations were undertaken before and after treatment according to Pouchitis Disease Activity Index. Remission was defined as a combination of Pouchitis Disease Activity Index clinical score ofor = 2, endoscopic score ofor = 1 and total Pouchitis Disease Activity Index score ofor = 4. The quality of life was assessed with the Inflammatory Bowel Disease Questionnaire.Fifteen of 20 patients (75%) achieved remission. The median total Pouchitis Disease Activity Index scores before and after therapy were, respectively, 14 (range 9-16) and 3 (range 2-10) (P0.001). The median Inflammatory Bowel Disease Questionnaire score also significantly improved from 105 (range 77-175) to 180 (range 85-220) (P0.001).Eight-week treatment with oral budesonide appears effective in inducing remission in patients with active pouchitis refractory to antibiotic treatment in this open-label study.

About two-thirds of patients with ulcerative colitis have an inflammatory involvement distal to the splenic flexure, and therefore may be effectively treated with topical treatment, allowing the delivery of the active drug directly to the site of inflammation and limiting systemic absorption and potential side-effects. Topical aminosalicylate therapy is the most effective approach, and most patients will benefit hugely, provided that the formulation reaches the upper extent of the disease. Therefore, the choice of topical preparation should be based on the proximal extent of the disease and on patient preference. Oral aminosalicylates are less effective than topical therapies; however, a combination of oral and topical aminosalicylates can be successful in refractory patients. Alternatives to aminosalicylates are the new glucocorticoids, budesonide and beclometasone dipropionate, either as enemas or oral formulations (only beclometasone dipropionate). A combination of oral or rectal new glucocorticoids with rectal aminosalicylates should be considered in patients refractory to either approach. When these measures fail, treatment with oral glucocorticoids is necessary. An intensive intravenous steroid regimen is also helpful for patients refractory to oral steroids. Alternative treatments include short-chain fatty acid enemas, nicotine enemas and patches, acetarsol suppositories, ciclosporin enemas and epidermal growth factor enemas. Several factors potentially having a negative impact on therapeutic response include concurrent enteric pathogens, coexistent irritable bowel syndrome, patient nonadherence to therapy, inadequate dosing and duration of therapy, and proximal progression of the disease. Surgical colectomy may be required in those rare patients refractory or intolerant to pharmacotherapy.

Severe colitis is a life-threatening complication of ulcerative colitis. Early recognition of the severity of the colitis and intensive treatment and monitoring have all contributed to improved outcome. Since their introduction in 1950s, corticosteroids are the first line therapy for severe active ulcerative colitis (UC). Several prognostic parameters (such as stools movement per day, C-reactive protein, increased amount of intestinal gas or small bowel dilation, hypoalbuminemia, fever etc) help the physician to quickly introduce cyclosporin or to refer the patient to the surgeon. This decision requires a careful evaluation of the patient and a medical /surgical team. Infliximab seems to be a promising drug but more controlled trial are needed.

To explore the efficacy and safety of the topically acting steroid beclometasone dipropionate (BDP) in an oral controlled release formulation in the treatment of extensive or left-sided ulcerative colitis.In a multicentre, randomised, parallel-group, single-blind study, patients with active mild to moderate ulcerative colitis were randomised to a 4-week treatment with BDP 5 mg/day o.d. vs. 5-ASA 0.8 g t.d.s. The primary efficacy variable was the decrease of Disease Activity Index (DAI) (clinical symptoms and endoscopic appearance of mucosa). Safety was evaluated by monitoring adverse events, vital signs, haematochemical parameters and adrenal function.One hundred and seventy-seven patients were enrolled and randomly treated with BDP (n = 90) or 5-ASA (n = 87). Mean DAI score decreased in both treatments groups (P0.0001 vs. baseline for both groups). Clinical remission was achieved in 63.0% of patients in the BDP group vs. 62.5% in the 5-ASA group. A significant DAI score improvement (P0.05) in favour of BDP was observed in patients with extensive disease. Both treatments were well tolerated. Mean plasma cortisol levels were significantly reduced vs. baseline in BDP recipients, but without signs of pituitary-adrenal function depletion.Oral BDP gave an overall treatment result in patients with active ulcerative colitis without signs of systemic side-effects.

Background: The pathogenesis of human ulcerative colitis (UC) is characterized by the presence of IL-13-producing Natural Killer T cells (NKT cells). One major complication of UC is the development of colitis-associated colorectal cancer. In these studies we determined the role of alternatively activated “M2 macrophages” in a new mouse model of colitis-associated carcinogenesis. Further, we verified these results through immunological analysis of surgical specimens obtained from patients with UC-associated colon cancer. Methods: Studies were performed using a mouse model for colitis-associated carcinogenesis based on chronic Oxazolonecolitis in combination with an initial i.p. azoxymethane (AOM) injection in female BALB/c mice. We observed chronic intestinal inflammation lasting for 12 weeks in mice repeatedly administered Oxazolone. Surgical specimens with UC-associated colon cancer were analyzed by flow cytometry and immunohistochemistry. Results: We could show that Oxazolone-colitis was mediated by colonic alpha-galactosyl-ceramide+CD1+ NKT-cells producing IL-13 and therefore resembles the immunological characteristics of human UC. Colon cancer development in this model was dependent on F4/80+CD11bhighGr1low macrophages producing IL-6 and EGF. Those cells inherited phenotypic characteristics of IL-13-stimulated alternativelyactivated “M2 macrophages”. To elucidate the importance of these “M2 macrophages”, we conducted bone marrow chimera studies and demonstrated that innate immune signaling through MyD88 in “M2 macrophages” is the key event for the production of tumor supporting factors like IL-6 and EGF. In surgical specimens obtained from patients with UC-associated colon cancer we verified those experimental findings. We consistently found a dense accumulation of IL-13-producing NKT cells inside the tumors. In addition, in this IL-13-dominated tumor micromilieu CD14+ and CD68+ antigen-presenting cells accumulated intensively and those antigen-presenting cells demonstrated an alternatively activated “M2 phenotype” by the expression of CD163 and CD205. Conclusions: We could demonstrate that in an experimental UC model, as well as in human UC, pathogenic IL-13producing NKT cells accumulate in the tumor micromilieu of UC-associated colon cancers. This immunologic situation inside the tumor microenvironment of mice and men induces tumor promoting M2 macrophages. Therefore M2 macrophages represent a potential target for future therapeutic strategies.

The meta-analyses of published trials have shown topical therapy with 5-aminosalicylic acid (5-ASA) to be the treatment of choice in active distal ulcerative colitis. Oral aminosalicylates are effective for both distal and extensive ulcerative colitis, but in distal colitis the rates of improvement and remission are usually lower than those reported for rectal 5-ASA therapy. An alternative to 5-ASA therapy is represented by the new steroids; budesonide and beclometasone dipropionate (BDP) enemas, the most extensively studied, have been shown to be as effective as conventional steroids but with a significantly lower inhibition of plasma cortisol. Patients who do not respond to 5-ASA or new steroids should be treated with oral steroids. Azathioprine or 6-mercaptopurine may be effective in patients who do not respond or cannot be weaned off steroids. Treatment of pouchitis is largely empirical and few controlled studies have been carried-out. Antibiotics are the treatment of choice and most patients make a good response to metronidazole or ciprofloxacin. Chronic refractory pouchitis may benefit from a prolonged course of a combination of antibiotics. Highly concentrated probiotics (VSL#3) are effective both for the prevention of pouchitis onset and the prevention of relapses.

The monitoring of patients with ulcerative colitis is easier than in patients with Crohn's disease for several reasons: the severity of symptoms and activity of inflammation tend to run parallel in ulcerative colitis when involvement of the large bowel is more extensive. The easy accessibility of the colonic mucosa by endoscopic and histologic examination provides further information concerning the degree of inflammation. In severe attacks, the patient must be admitted to hospital and monitored carefully. Clinical and laboratory parameters (such as daily stools, CRP, fever, haemoglobin, albumin, etc.) and plain abdominal X-ray are useful in monitoring the activity of the disease and to predict the outcome. In mild to moderate attacks, endoscopic and histologic evaluation are the best methods for choosing the appropriate treatment and for assessing response.

Refractoriness to conventional therapy is a common and intriguing problem in Crohn's disease patients. At the present time there is no agreement on its definition and several mechanisms are involved in its determination. Immunosuppressors, such as azathioprine (AZA), 6-mercaptopurine (6MP) and methotrexate (MTX) are effective drugs for controlling the inflammatory process and avoid chronic glucocorticosteroid treatment and its related side-effects. Recently, the introduction of tumour necrosis factor antibodies (infliximab) has dramatically changed the natural history of Crohn's disease and its therapeutic approach. Several studies have determined the efficacy, mechanisms and safety of infliximab. However, this molecular approach has also left several questions unanswered about the mechanisms of refractoriness, possible concomitant treatments and long-term safety and efficacy.

Preliminary data suggest that short-term antibiotic therapy with a single drug is effective for the treatment of patients with pouchitis. However, some patients are resistant to treatment.To evaluate the therapeutic efficacy of a prolonged course of a combination of two antibiotics in patients with refractory or recurrent pouchitis, as well as its impact on their quality of life.Patients with active refractory or recurrent pouchitis were recruited. This was defined as both: (i) a history of pouchitis at least twice in the last 12 months or persistent pouchitis requiring continual intake of antibiotics; and (ii) a Pouchitis Disease Activity Index score 3 7 (best to worst pouchitis=0-18) at the beginning of therapy. Treatment consisted of a combination of metronidazole, 400 or 500 mg twice daily, and ciprofloxacin, 500 mg twice daily, for 28 days. Symptomatic, endoscopic and histological evaluations were undertaken before and after antibiotic therapy using the Pouchitis Disease Activity Index score. Remission was defined as a combination of a Pouchitis Disease Activity Index clinical score ofor= 2, endoscopic score ofor= 1 and total score ofor= 4. The quality of life was assessed with the Inflammatory Bowel Disease Questionnaire, which encompasses bowel, systemic and emotional symptoms as well as social function (worst to best=32-224).Forty-four patients (24 male, 20 female; median age, 37.5 years) entered the trial and completed treatment. Thirty-six (82%) went into remission. The median Pouchitis Disease Activity Index scores before and after therapy were 12 (range, 8-17) and 3 (range, 1-10), respectively (P0.0001). The median Inflammatory Bowel Disease Questionnaire score also significantly improved from 96.5 (range, 74-183) to 175 (range, 76-215) with this therapy (P0.0001). The eight patients (five male, three female) who did not go into remission were significantly older (median 47.5 vs. 35 years; P=0.007), had a longer history of pouchitis (95.5 vs. 26 months; P=0.0008), had a greater proportion with chronic pouchitis (chronic/relapsing: 6/2 vs. 9/27; relative risk, 1.6; 95% confidence interval, 1.0-2.4) and tended to have a higher Pouchitis Disease Activity Index score before treatment (median 14.5 vs. 12; P=0.13) than those who went into remission. Even in these eight patients, the median Pouchitis Disease Activity Index score significantly improved from 14.5 (range, 8-16) to 9.5 (range, 7-10) (P=0.0078), as did the Inflammatory Bowel Disease Questionnaire score from 95.5 (range, 74-134) to 127 (range, 76-187) (P=0.039). The Inflammatory Bowel Disease Questionnaire score strongly correlated with the Pouchitis Disease Activity Index score (r=0.79, P0.0001), and was significantly related to the patients' overall assessment of satisfaction (P0.0001). No serious side-effects were noted.Four-week treatment with a combination of metronidazole and ciprofloxacin is highly effective in patients with active recurrent or refractory pouchitis, objectively improving the inflammation and quality of life. The Inflammatory Bowel Disease Questionnaire is a sensitive tool for evaluating patients with pouchitis, and correlates well with disease activity.

To evaluate efficacy and safety of oral beclometasone dipropionate (BDP) when added to 5-ASA in the treatment of patients with active ulcerative colitis.In a 4-week, placebo-controlled, double-blind study, patients with extensive or left-sided mild to moderate active ulcerative colitis were randomized to receive oral 5-ASA (3.2 g/day) plus BDP (5 mg/day) or placebo. Clinical, endoscopic and histologic features, and haematochemical parameters were recorded at baseline and at the end of the study.One hundred and nineteen patients were enrolled and randomly treated with BDP plus 5-ASA (n = 58) or placebo plus 5-ASA (n = 61). Both treatment groups showed a statistically significant decrease of disease activity index (DAI) and histology score at the end of treatment (P = 0.001, each). DAI score was lower in the BDP group than in the placebo group (P = 0.014), with more patients in clinical remission in the BDP group (58.6% vs. 34.4%, P = 0.008). Serum cortisol levels significantly decreased in BDP group vs. baseline (P = 0.002), but without signs of pituitary-adrenal function depletion. A low incidence of adverse events was observed in both groups.Oral BDP in combination with oral 5-ASA is significantly more effective than 5-ASA alone in the treatment of patients with extensive or left-sided active ulcerative colitis.

Oral and topical mesalazine formulations are effective in active ulcerative colitis, but little is known on the efficacy of combined treatment.To compare the efficacy of oral mesalazine vs. combined oral and topical mesalazine in mildly to moderately active ulcerative colitis.Patients with mildly to moderately active ulcerative colitis (Clinical Activity Index, CAI 4-12) were identified at 15 participating centres. They were randomized to receive either mesalazine 4 g orally plus placebo enema, or mesalazine 2 g orally plus mesalazine 2 g rectally as a liquid enema for 6 weeks. The rate of clinical remission (CAI4) or clinical remission/improvement (reduction of CAI of 50% from baseline) at 6 weeks and time to clinical remission/improvement were primary end-points; the rate of endoscopic remission was a secondary end-point.67 patients were assigned to oral treatment and 63 to combined treatment. One patient in the oral group and 2 in the combined group discontinued the treatment due to adverse events. Following an intention-to-treat analysis, the rate of clinical remission was 82% for oral treatment and 87% for combined treatment (P=0.56); the mean time to remission 22.2 and 20.2 days, respectively (P=0.29); the rate of clinical remission/improvement and the rate of endoscopic remission were 85% and 91% (P=0.503) and 58% and 71% (P=0.21), respectively.In patients with mild active ulcerative colitis, mesalazine 4 g orally and 2 g orally plus 2 g enema are equally effective in inducing disease remission.

Restorative proctocolectomy with ileal pouch anal anastomosis is the first choice procedure for the treatment of ulcerative colitis and familial adenomatous polyposis. The introduction of the stapled technique has shortened the duration of the procedure and reduced the complication rates. Data on 335 consecutive patients undergoing ileal pouch anal anastomosis for ulcerative colitis (277 pts), Indeterminate colitis (20 pts) and familial adenomatous polyposis (38 pts) between 1984 and 1998 were prospectively collected. Parameters evaluated included diagnosis, surgical technique, functional outcome, early and late complications and their management and results. Twenty-nine patients (8.6%) presented with pelvic sepsis. Twelve patients (3.5%) experienced late perianal fistulas. The pouch failure rate was 3.4%. Six patients required a re-do pouch procedure, with 75.9% preservation of sphincter function. No correlation was found between complication rates and diagnosis. The mean number of stools was 5.2/24 h. The study confirmed the safety and effectiveness of the procedure. In particular, morbidity rates are comparable to those of major abdominal procedures and the long-term functional results are satisfactory. However, a number of technical aspects, such as the anastomosis technique, the need for temporary ileostomy and the treatment of indeterminate colitis, still remain controversial.

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.

Although 5-aminosalicylic acid (5-ASA) oral compounds are the standard maintenance treatment for ulcerative colitis in remission, some patients cannot use them because of side-effects. Clinical and experimental observations have suggested the potential role of probiotics in inflammatory bowel disease therapy.To evaluate the effects on intestinal microflora and the clinical efficacy of a new probiotic preparation in patients with ulcerative colitis in remission.Twenty patients with ulcerative colitis, intolerant or allergic to 5-ASA, have been treated with a new probiotic preparation (VSL#3, CSL, Milan, Italy) containing 5x10(11) cells/g of 3 strains of bifidobacteria, 4 strains of lactobacilli and 1 strain of Streptococcus salivarius ssp. thermophilus. Two doses of 3 g were administered o.d. for 12 months. Faecal samples for stool culture were obtained from the patients at the beginning of the trial and after 10, 20, 40, 60, 75, 90 days, 12 months and at 15 days after the end of the treatment. The following bacterial groups have been evaluated in the faeces: total aerobic and anaerobic bacteria, enterococci, Streptococcus thermophilus, lactobacilli, bifidobacteria, Bacteroides, clostridia, coliforms. Patients were assessed clinically every two months, and assessed endoscopically at 6 and 12 months or in relapse.Faecal concentrations of Streptococcus salivarius ssp. thermophilus, lactobacilli and bifidobacteria increased significantly in all patients, compared to their basal level, from the 20th day of treatment (P0.05) and remained stable throughout the study. Concentrations of Bacteroides, clostridia, coliforms, total aerobic and anaerobic bacteria did not change significantly during treatment (P = N.S.). Fifteen of 20 treated patients remained in remission during the study, one patient was lost to follow up, while the remaining relapsed. No significant side-effects have been reported.These results show that this probiotic preparation is able to colonize the intestine, and suggest that it may be useful in maintaining the remission in ulcerative colitis patients intolerant or allergic to 5-ASA. Controlled trials are warranted to confirm these preliminary results.

A new mesalazine rectal gel preparation (without propellant gas) has been recently developed to improve topical treatment in distal ulcerative colitis.To evaluate the efficacy, safety and patient tolerability of mesalazine gel enema compared with mesalazine foam enema in the treatment of patients with acute left-sided ulcerative colitis.In a randomized multicentre investigator-blind parallel group trial, 103 patients with mild to moderate left-sided colitis or proctosigmoiditis were randomly allocated to mesalazine 2 g gel enema (n = 50 evaluable patients) and mesalazine 2 g foam enema (n = 53 evaluable patients) for 4 weeks. Clinical symptoms, endoscopic and histological findings were assessed at entry, 2 and 4 weeks. Patients' evaluation of treatment tolerability and acceptability was assessed at 2 and 4 weeks.After 4 weeks of treatment, clinical remission was achieved by 76% of mesalazine gel enema-treated patients and 69% of patients treated with mesalazine foam enema (P = 0.608). Endoscopic remission rates at week 4 were 51 and 52% for the mesalazine gel and foam enemas, respectively (P = 0.925). Histological remission was achieved by 30% of patients in both groups. Patients reported that the new mesalazine gel preparation was significantly better tolerated than the foam enema. Patients in the foam group had significantly more difficulty in retention (25% vs. 6%, P0.05), abdominal bloating (50% vs. 26%, P0.005) and discomfort during administration (48% vs. 26%, P0.05).The new mesalazine gel enema is efficacious and significantly better tolerated than the mesalazine foam enema.

Budesonide is a corticosteroid with high topical anti-inflammatory activity and low systemic activity due to rapid inactivation. We have assessed the efficacy and safety of an oral controlled ileal release (CIR) preparation of budesonide for maintenance of remission in patients with ileal or ileocaecal Crohn's disease.In a double-blind, multicentre trial, 75 patients in clinical remission (Crohn's Disease Activity Index, CDAI,or = 150) were randomly assigned to receive placebo, budesonide 3 mg or budesonide 6 mg daily for 12 months. Trial drugs were given at a fixed dose and without concomitant medication. The primary outcome measure was relapse, defined as a CDAI150 together with an increase of at least 60 units from entry. A patient was also considered to have a relapse if withdrawn from the study due to clinical deterioration, whether or not a CDAI value could be calculated at that time.There were no statistically significant differences in the relapse rate at any time-point throughout the study. By 12 months the proportion of patients having relapsed were 48, 46 and 60% in those patients treated with budesonide 6 mg, 3 mg and placebo, respectively (N.S.). Treatments were well tolerated, and the proportion of patients with suppressed adrenal function (according to predetermined criteria) were 50% (6 mg), 26% (3 mg) and 17% (placebo) (P = 0.096).In the present study, relapse rate and time to relapse were similar in the patients treated with budesonide CIR, 6 mg daily or 3 mg daily or with placebo, throughout 12 months. This is in contrast to the two previous trials with identical design, where a significant effect of budesonide CIR in prolonging the median time to relapse was found. Possible reasons for the negative results of the present study include small sample size, and the fact that there was a high placebo response.

A multicenter double-blind placebo-controlled clinical study was conducted to evaluate the efficacy and tolerability of two different therapeutic schedules of mesalazine suppositories in patients with ulcerative proctitis.From 1990 to 1993, 111 patients with ulcerative proctisis in remission, limited to the rectum (or = 15 cm from anus), were enrolled. After obtaining informed consent, patients were randomized to three treatment groups: 500 mg mesalazine b.i.d. (36 patients), 500 mg mesalazine u.i.d. (40 patients), and placebo (35 patients). The treatment lasted 1 yr. Follow-up consisted of periodic clinical, endoscopic, and histological assessments. An endoscopic score1 according to the Baron scale defined relapse occurrence. The three groups were homogeneous as regards main demographic, diagnostic, and prognostic features.The cumulative relapse rates at 12 months were 10% (95% confidence interval [CI]: 0-21) in the mesalazine b.i.d. group, 32% (95% CI: 16-49) in the mesalazine u.i.d. group, and 47% (95% CI: 29-65) in the placebo group. The comparison between the mesalazine b.i.d. group and the mesalazine u.i.d. group cumulative relapse rates gave a p value of 0.0334, whereas the corresponding comparison between the mesalazine b.i.d. group and the placebo group gave a p value of 0.007 (log-rank test). The dose-response relationship was statistically significant (p = 0.008 by Cox analysis). Two patients in the mesalazine b.i.d. group, two patients in the mesalazine u.i.d. group, and one patient in the placebo group withdrew from the study due to nonserious adverse events; four, three, and four patients per group, respectively, dropped out because of poor compliance. Two patients in the mesalazine u.i.d. group and two in the placebo group were lost to follow-up.The results of this study confirm the therapeutic efficacy of mesalazine suppositories in the maintenance treatment of ulcerative proctitis. According to our experience the most effective therapeutic schedule is 500 mg mesalazine b.i.d.

Objectives: To determine the concentrations of interleukin-1 beta, interleukin-6, and interleukin-8 in tissue homogenates of mucosal biopsy specimens from Helicobacter pylori-positive and -negative patients. Methods: In 43 consecutive patients who underwent upper gastrointestinal endoscopy, seven antral biopsies were taken; three specimens were used for cytokine determination and the remaining four biopsies were processed for H. pylori detection. Peripheral venous blood was collected and IgG to H. pylori was assayed by an ELISA technique. Results: Twenty-nine of 43 patients (67%) were histologically positive for H. pylori; all had chronic gastritis. The mucosal levels of interleukin-6 and interleukin-8 were significantly higher in H. pylori-positive patients than in the negative patients (p < 0.001). A significantly higher percentage of interleukin-8 was found in patients colonized by H. pylori with active superficial chronic gastritis (85.7%), compared to quiescent superficial gastritis (12.5%) (p < 0.01), and the median and range were, respectively, 400 (0-1000) and 0 (0-200) pg/mg protein (p < 0.001). In patients with active superficial gastritis, a significant correlation between interleukin-6 and -8 was found (p 0.01). No difference was found regarding the mucosal levels of interleukin-1 beta according to the presence of H. pylori. Conclusions: These results suggest a possible pathogenetic role for interleukin-6 and interleukin-8 in H. pylori-associated gastritis.

Steroids are very useful drugs in the treatment of active Crohn's disease (CD), but clinical relapses after steroid withdrawal may be very high. We investigated the efficacy of two steroid regimens of different duration in inducing remission and in maintaining it after drug suspension. Patients with active CD were randomly assigned to scheme A, lasting 7 weeks (27 patients), or to scheme B, lasting 15 weeks (27 patients). Remission rates at the end of the treatment were 81% for scheme A and 85% for scheme B. Relapse rates at 6 months after stopping the treatment were 50% (11 patients) and 52% (12 patients), respectively. Remission rates seem not to be influenced by the duration of the treatment, but patients recently treated with steroids showed a higher relapse rate if they received the short-duration treatment.

Levels of zinc in plasma from patients with Crohn's disease were significantly lower than those of sex and age matched controls. We also measured the level of plasmic thymulin, a hormone released by the thymus gland, which in its active form binds one zinc molecule. The zinc unbound form of thymulin is biologically inactive and its level in the blood is a very sensitive marker of even marginal zinc deficiency. Levels of active thymulin were significantly reduced in plasma from patients with Crohn's disease, whereas plasma concentrations of the inactive form was higher than in controls. The in vitro addition of zinc ions restored thymulin activity in plasma from patients with Crohn's disease, and induced the disappearance of the inactive form. These findings suggest the existence of a zinc dependent alteration regarding the biological function of thymic hormones in patients with Crohn's disease. Such a defect might explain some of the immunological abnormalities observed in these pathological conditions.

In 34 consecutive patients in whom the diagnosis of Hirschsprung's disease (HD) was suspected, the reliability of clinical symptoms, radiological parameters, and anorectal manometry was retrospectively and blindly evaluated by three independent investigators. In 19 patients the diagnosis of HD was histologically proved, while in the remaining 15 cases the diagnosis of idiopathic constipation was justified by persistent success of medical treatment at regular follow-up. Anorectal manometry was correctly diagnostic in all the patients who were examined. The recto and inhibitory reflex, recorded in all the patients with idiopathic constipation was absent in patients suffering from HD. Moreover, other manometric parameters, peculiar to HD were found: a significant lower anal resting pressure and pain threshold, as well as a decreased frequency of spontaneous rhythmic oscillations. The reliability of radiological and clinical data for these diagnoses appeared to be inadequate. Therefore, the diagnosis of HD can be confidently stated only on the basis of manometric investigations.

Constipation is a symptom common to many and different dis eases. It is due, at any rate, to an altered transit of intestinal contents, but it can be a secondary symptom in an organic intestinal and extraintestinal disease, or it can be caused by a primary motor disorder of the bowel. Also in this latter case constipation may be either the main or the only symptom, or it may belong to the wide range of the irritable bowel syndrome. On the other hand, even the definition of constipation is controversial: constipation may be defined as a reduced frequency of evacuations, as a difficulty in stools expulsion or as expulsion of too small stools. For all these reasons, the patients suffering from constipation do not make a homogeneous group. The studies aiming at investigating the intestinal motor alterations responsible for constipation, should consider this problem and should therefore be carried out for cases selected according to clear nosological criteria.

Production of leucocyte migration inhibition factor by peripheral blood leucocytes in response to challenge with gluten fractions has been proposed as a reliable in vitro test for the diagnosis of coeliac disease. We have performed the leucocyte migration inhibition test with two different gluten fractions, GFIII and B2, in untreated and treated coeliac patients, patients with other intestinal diseases (abnormal controls) and healthy controls, and evaluated the sensitivity, specificity and positive and negative predictability of the test for the diagnosis of coeliac disease. Using GFIII as antigen leucocyte migration was significantly inhibited, compared to healthy controls, not only in treated and untreated coeliacs but also in abnormal controls. Using B2 gluten subfraction as antigen only treated coeliacs and abnormal controls differed significantly from healthy controls. The elevated number of abnormal controls showing migration inhibition consistently affected the diagnostic value of the test, which did not vary using B2 subfraction instead of GFIII as antigen. Our study confirms previous observations of gluten sensitization, as detected by leucocyte migration inhibition, in coeliac patients but strongly questions the claim that coeliac disease can be diagnosed on the basis of a positive leucocyte migration inhibition test without the need for intestinal biopsy.

The role of allergic responses to dietary antigens in the pathogenesis of inflammatory Bowel Disease (IBD) remains speculative. We studied 50 patients with Ulcerative Colitis (UC), 50 patients with Crohn's Disease (CD) and 100 healthy controls (HC) matched for sex and age. In these patients total serum IgE and specific IgE to ten selected foods were estimated using Phadebas PRIST and RAST. There was no significant difference in the total serum IgE level between UC, CD and HC. The percentage of positive reaction to specific IgE was significantly lower in HC (score 1-2: 7%; score 2: 3%) compared with UC (score 1-2: 24%, p less than 0.004; score 2: 8%, n.s.) and CD (score 1-2: 16%, n.s.; score 2: 12%, p less than 0.03). In CD with colic or ileocolic involvement, the percentage of patients with a positive response to RAST was significantly greater (score 1-2: 26%; score 2: 21%) than in CD with ileal involvement. The considerable increase in positive results to RAST in IBD may be due to a greater absorption of antigens through the diseased wall.

Malnutrition is frequently reported in chronic diseases with involvement of gastrointestinal tract, such as Crohn's disease; however, information about this problem is scarce, and available only for hospitalized patients with severe disease. The aim of this study was to evaluate the nutritional status of 44 consecutive outpatients with Crohn's disease in remission or in a stage of low activity (CDAI less than 250). Eighteen of the patients weighed less than 90% of ideal weight and 5 of these weighed less than 80%. Triceps skinfold, a measure of fat store, was less than or equal to 15th percentile in 30%; arm muscle circumference, indicative of muscle mass, was less than or equal to 15th percentile in 59%. The alteration of weight and arm muscle circumference was greater in patients with midly active disease (p less than 0.005) and in those with ileal and ileocolic involvement. Caloric intake, assessed by a seven day questionnaire, was generally good (35.9 +/- 11 Kcal/kg ideal weight/day) and sufficient to maintain weight. Creatinine height index was elevated in 55% of the whole group. Serum albumin was decreased in only 2 cases, and haemoglobin in only 4. Our results show that malnutrition is a serious problem also in outpatients with Crohn's disease. Anthropometric parameters are more sensitive indicators than conventional laboratory studies.

Background Crohn’s disease (CD) is a chronic, relapsing and remitting inflammatory bowel disease. The relationship of attachment to the illness is considered to be bidirectional. Objective The authors investigated aspects of this bidirectional relationship. Method A group of 102 patients with CD and 306 healthy subjects filled out the Attachment Style Questionnaire and the Parental Bonding Instrument. Results Patients with CD exhibit a predominantly insecure attachment and perceived their parents’ behaviors as characterized by low maternal care and high paternal overprotection. Discussion The evaluation of attachment style and early parental experiences in patients with CD may shed light on the bidirectional relationship between attachment and illness. These findings may confirm the bidirectional relationship between insecure attachment and chronic illness.

Background Previous studies have shown a relationship between inflammatory bowel disease (IBD) and psychological stress. Adverse parenting is recognized as an important risk factor for the development of psychiatric disorders in adulthood. Objective The authors sought to further investigate this relationship by clarifying aspects of the bonding relationship in IBD patients and control subjects. Method A group of 307 patients with IBD and a group of 307 healthy subjects filled out the questionnaire Parental Bonding Instrument. Results Patients with IBD perceived their parents’ behaviors as characterized by low care and paternal overprotection; the category Optimal Parenting differs highly in the two samples. Conclusion This study demonstrated an association between inadequate parenting and a chronic physical illness. These findings are consistent with a growing literature that links early parental experience to chronic illness.

Background: Ulcerous rectocolitis and Crohn’s disease are the best known forms of inflammatory bowel disease (IBD). Skin manifestations are not uncommon in IBD and may be divided into specific cutaneous signs, aspecific cutaneous signs, and cutaneous signs caused by drugs used for IBD therapy. The specific signs (fistulas, rhagades and ulcers) are the result of the diffusion of the intestinal inflammatory process into the skin. Aspecific cutaneous signs (stomatic aphthosis, erythema nodosum, pyoderma gangrenosum, Sweet’s syndrome, vasculitis, bullous diseases) are quite frequently found in those suffering from IBD, but also in apparently healthy subjects, and may sometimes be the first sign of the intestinal disease. Cutaneous manifestations due to drugs vary in clinical aspect and are the direct consequence of the therapies adopted, which in IBD patients can be quite numerous: steroids, immunosuppressants, 5-aminosalicylic acid, biological agents, antibiotics. Objective and Methods:Due to the frequent finding of cutaneous manifestations in patients affected by IBD, a collaboration was set up between the Dermatological Clinic of the University of Bologna and the Center for the Study of IBD of the same university hospital. The aim was to diagnose the cutaneous signs appearing during IBD and to establish their etiopathogenesis in order to assess whether they were the result of epiphenomena of the IBD or side effects of the therapies adopted. Results: The cutaneous manifestations we observed can be divided into three distinct groups: signs that were specific to the basic disease, aspecific signs and finally signs attributable to the drugs used for therapy. Particular attention was given to the aspecific signs and those consequential to therapy. The aspecific cutaneous signs seen in our clinic generally reflect those reported in the literature. The cutaneous manifestations due to drugs were further divided into three groups: rosacea, acneiform dermatitis and psoriasis-like dermatitis. The most notable aspect of our series is the high number of patients presenting psoriasiform-type dermatitides with a generally widespread diffusion. Conclusion: We would like to draw attention to the fact that all patients with psoriasis had been undergoing treatment with drugs inhibiting tumor necrosis factor α (TNF-α) as part of IBD therapy. In all cases, the cutaneous reaction started after the third or fourth infusion of the biological drug. Anti-TNF-α agents have also been successfully used to treat psoriasis in the last few years. The reason for this apparently paradoxical effect of the therapy is still unclear.