Suppressive effect of 1,25-dihydroxyvitamin D3 and its analogues EB 1089 and KH 1060 on T lymphocyte proliferation in active ulcerative colitis.

This study examined the effect exerted by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and two vitamin D analogues, EB 1089 and KH 1060, on the proliferation of T lymphocytes obtained from ulcerative colitis (UC) patients and healthy controls. The proliferative response of T lymphocytes to phytohaemagglutinin treatment was first analyzed on days three, five, and seven of culture. Cell proliferation was significantly lower in UC patients than that observed in healthy controls. The highest proliferation value, in either controls or patients, was registered on day five of culture. On day seven, a decrease in proliferation occurred, less evident in patients with respect to controls, whereas on day three, controls and patients showed the same proliferation value. The response of T lymphocytes of either healthy controls or UC patients to 1,25(OH)2D3, EB 1089, or KH 1060 was then investigated, treating the cells for three, five, and seven days with 10 nM vitamin D derivatives. In the presence of these compounds, cell proliferation was significantly inhibited in both groups, but on day seven, the inhibition of lymphocyte proliferation was remarkable in controls, whereas in patients it was similar to that registered on day five. The highest inhibition values were always obtained in the presence of KH 1060, and the time dependence was continuous in controls, but in the presence of EB 1089 only in patients. T lymphocytes prepared from healthy controls and UC patients were then cultured for five days in the presence of vitamin D derivatives at three different concentrations (0.1, 1, and 10 nM). In the two groups, a dose-dependent inhibition was registered in the presence of 1,25(OH)2D3 or EB 1089, while the inhibition of proliferation exerted by KH 1060 was not dose-dependent. The results obtained suggest an option for the use of the two non-hypercalcemic vitamin D analogues in the therapy of UC patients, perhaps in association with other immunosuppressive drugs.

Oral mesalazine (5-aminosalicylic acid; Asacol) for the prevention of post-operative recurrence of Crohn's disease. Gruppo Italiano per lo Studio del Colon e del Retto (GISC).

METHODS: A multicentre randomized controlled trial was conducted to evaluate the efficacy of oral mesalazine (5-aminosalicylic acid) for the prevention of post-operative recurrence in 110 patients operated on for Crohn's disease by first intestinal resection. Patients were randomly allocated to receive 2.4 g/day of mesalazine, or no treatment at all. The protocol included colonoscopy with ileoscopy at 6 months and yearly thereafter. Recurrence was defined on the basis of endoscopic criteria and classified as mild or severe. RESULTS: The demographic and pre-trial characteristics were very similar in the two groups of patients. The cumulative proportion of recurrence at 6, 12 and 24 months was significantly lower in the mesalazine group than in untreated group (P = 0.002). At 24 months the cumulative proportions of endoscopic recurrence were 0.52 +/- 0.12 (+/- S.E.M.) and 0.85 (+/- 0.07), respectively. At the same time the cumulative proportions of symptomatic recurrence were 0.18 +/- 0.09 and 0.41 +/- 0.09 (P = 0.006). The cumulative proportions of the severe recurrence was also significantly lower in the mesalazine group (0.17 +/- 0.09 vs. 0.38 +/- 0.09; P = 0.021). CONCLUSIONS: The preliminary results of this study show that administration of oral mesalazine soon after surgery is effective in preventing post-operative endoscopic recurrence in Crohn's disease over a 2-year period. It is estimated that this treatment prevents 39% of all recurrences and 55% of the severe recurrences.

Oral beclometasone dipropionate in the treatment of extensive and left-sided active ulcerative colitis: a multicentre randomised study.

AIM: 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. METHODS: 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. RESULTS: 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 (P < 0.0001 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 (P < 0.05) 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. CONCLUSION: Oral BDP gave an overall treatment result in patients with active ulcerative colitis without signs of systemic side-effects.

Beclomethasone dipropionate enemas versus prednisolone sodium phosphate enemas in the treatment of distal ulcerative colitis.

AIM: To compare beclomethasone dipropionate 3 mg/60 mL enema (BDP) and prednisolone sodium phosphate 30 mg/60 mL enema (PP) once daily in patients with active distal ulcerative colitis. METHODS: One hundred and fifty-seven patients were enrolled in a multicentre, 4-week, randomized, double-blind trial. Patients were assessed at baseline, 2 and 4 weeks. RESULTS: Both treatment groups showed statistically significant improvement of clinical activity after 2 and 4 weeks. Endoscopy and biopsy showed a reduction in the activity score at the end of the treatment period in both groups. No statistically significant difference was observed between the two treatment groups. After 4 weeks, 29% of patients in the BDP group and 25% in the PP group were considered to be in clinical remission; an improvement was observed in 40% of patients on BDP and in 47% on PP. Mean morning plasma cortisol levels showed a slight but significant reduction in the PP group, while the ACTH test showed that neither drug interfered with the hypothalamic-pituitary-adrenal (HPA) axis function. No significant changes were observed in the laboratory tests. Finally, there was a low incidence of adverse events in both groups. CONCLUSIONS: It is concluded that, in the topical treatment of active distal ulcerative colitis, BDP 3 mg enemas are as efficacious as PP 30 mg enemas, without interference with the HPA axis.

A new mesalazine gel enema in the treatment of left-sided ulcerative colitis: a randomized controlled multicentre trial.

BACKGROUND: A new mesalazine rectal gel preparation (without propellant gas) has been recently developed to improve topical treatment in distal ulcerative colitis. AIM: 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. METHODS: 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. RESULTS: 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%, P < 0.05), abdominal bloating (50% vs. 26%, P < 0.005) and discomfort during administration (48% vs. 26%, P < 0.05). CONCLUSION: The new mesalazine gel enema is efficacious and significantly better tolerated than the mesalazine foam enema.

Oral and topical 5-aminosalicylic acid (mesalazine) in inducing and maintaining remission in mild-moderate relapse of ulcerative colitis: one-year randomised multicentre trial.

BACKGROUND: The association of oral 5-aminosalicylic acid (mesalazine) and enema is effective in treatment of mild-moderate forms of ulcerative colitis. However no study has been aimed at determining optimal duration of this association in active ulcerative colitis. AIM: To determine whether longer duration of therapy: 1. increases the rate of patients achieving remission, and 2. reduces relapse rate during the maintenance period in patients in remission. PATIENTS AND METHODS: A total of 149 patients, (89 male, 60 female), were randomly assigned to a regimen with 5-aminosalicylic acid tablets 2.4 g/day associated with 5-aminosalycilic enema 2 g/day for a 4-week (n = 73) or 8-week regimen (n = 76). After this acute therapy, patients were submitted to clinical, endoscopic and histological examinations and those in remission were assigned to a follow-up (maintenance) period with oral mesalazine alone at a dosage of 1.2 g/day. A clinical visit, including laboratory tests, at 6 months and an endoscopic-histological control at 12 months were carried out to exclude symptoms and endoscopic-histological signs of activity. Relapse of disease, i.e., presence of clinical symptoms or abnormal laboratory tests, was confirmed by endoscopy and histology. RESULTS: At end of acute phase, clinical, endoscopic and histological remission was comparable in the two groups: 42/76 (55%), in the 4-week, and 47/73 patients (64%), in the 8-week regimen. No difference was found stratifying patients according to extension of disease. Of these 89 patients in remission, 75 (34 from 4-week regimen; 41 from 8-week regimen) completed 12 months' follow-up. At end of follow-up, a similar percentage of patients in the 4-week regimen (50%) and 8-week regimen (51%) were still in remission. No significant difference between cumulative relapse rates of the two groups was found. Stratifying patients according to extension of disease, in the 8-week regimen group, those with left-sided colitis showed a higher remission rate than that of patients with diffuse colitis (66% versus 35%, p < 0.05). All regimens were well tolerated by most patients during the entire study period. CONCLUSIONS: An additional 4 weeks of topical treatment does not increase the remission rate in patients with mild-moderate active ulcerative colitis but seems to reduce the probability of relapse in patients with left-sided colitis.

The double contrast barium enema in the identification of proximal colonic adenomas and carcinomas beyond the limits of fiberoptic sigmoidoscopy.

Eight hundred and twenty patients were examined by fiberoptic sigmoidoscopy (SIG) and double contrast barium enema (DCBE) to detect colonic cancers or adenomas. Cancer or adenoma in the bowel tract proximal to the upper limit of SIG insertion was detected in 4 patients and in 12 on DCBE. The DCBE detection rate of proximal colonic lesions varied according to the hemoccult (HO) outcome. This was 1.16% for cancer and 2.03% for adenoma in HO+ patients and null for cancer and 1.23% for adenoma in HO- patients. The detection rate of proximal adenomas was higher in patients who presented adenomas on endoscopy in the distal bowel (SIG+), 2.46% as compared to 0.48% in SIG- patients, independent of the HO reports. Routine DCBE is practically useless in HO-SIG- patients and questionable in HO-SIG+ patients since improvement of the detection rate is null for cancer and moderate for adenoma. It is recommended for HO+ patients because it increases the colonic cancer detection rate (10.5% in this study).

Better quality of therapy with 5-ASA colonic foam in active ulcerative colitis. A multicenter comparative trial with 5-ASA enema.

We evaluated the efficacy, tolerance, and acceptance of a new 5-ASA colonic foam versus 5-ASA liquid enema in the short-term treatment of active ulcerative colitis in a three-week prospective, randomized, investigator-blind study, enrolling 233 patients from 12 outpatient clinics in Italy. In arm 1 of the study, 117 patients with mild attacks received 2 g of 5-ASA as foam or enema at bedtime. In arm 2, 116 patients with moderate attacks were given 4 g of 5-ASA as foam or enema at bedtime. End points were defined as complete relief of symptoms, and endoscopic and histological evidence of remission or improvement. In patients with mild relapse, 34 of 63 (54%) treated with foam were in clinical remission after only 10 days compared with 17 of 51 (31%) treated with enemas (P < 0.05). However, there was no statistically significant difference between foam (83%) and enema (74%) after three weeks. In patients with moderate relapse, a higher proportion of patients achieved complete clinical remission in the foam group (63%) compared with enema group (52%) after three weeks (difference 11%, 95% CI -7 to 29). No significant differences were observed in endoscopic and histological evaluation of colonic mucosa between treatment groups in either arm. 5-ASA foam was well tolerated. No unexpected adverse events were reported. Patient evaluation of therapy showed that foam was much better accepted than enema because foam was more comfortable, more practical, easier to retain, and interfered less with daily living.(ABSTRACT TRUNCATED AT 250 WORDS)

Defined-formula diets versus steroids in the treatment of active Crohn's disease: a meta-analysis.

BACKGROUND: To compare the effectiveness of defined-formula diets versus steroids for the treatment of active Crohn's disease, we conducted a meta-analysis of the published clinical trials. METHODS: Standard techniques for literature search were used to identify the pertinent trials. All studies included in our meta-analysis (n = 7) were aimed at comparing defined-formula diets versus steroids, using a randomized design. The patient-specific end-point of the meta-analysis was the occurrence of a treatment failure. RESULTS: Our meta-analysis indicated that steroids are more effective than defined-formula diets for inducing remission in active Crohn's disease. In fact, the relative risk of treatment failure (RTF) was significantly lower in the steroid group than in the diet group (risk values for patients given steroids compared with patients given diet: a) method of Mantel-Haenszel: RTF = 0.35; 95% confidence interval, 0.23-0.53; p < 0.001; b) method of Der Simonian & Laird: RTF = 0.43; 95% confidence interval, <0-0.94; p = 0.03). A separate analysis was carried out in which only the subgroup of patients who were not intolerant to diet were evaluated; this analysis also showed a superiority of steroids over diet. CONCLUSIONS: The data examined in this meta-analysis do not support the use of diets as primary treatment for acute exacerbations of Crohn's disease in adults.

Intermittent therapy with high-dose 5-aminosalicylic acid enemas for maintaining remission in ulcerative proctosigmoiditis.

Sixty patients who had presented recently with a relapse of mild to moderate ulcerative colitis with rectosigmoid involvement were randomly assigned to treatment with either 5-aminosalicylic acid enemas (N = 29) or oral sulfasalazine (N = 31). All patients were in remission, which was documented by clinical, histologic, and endoscopic criteria. Five-aminosalicylic acid treatment was administered on an intermittent schedule, consisting of 4 gm daily for the first seven days of each month; sulfasalazine was given as continuous therapy (2 gm daily as oral tablets). The study period was 2 years. Overall, 9 relapses occurred in the 5-aminosalicylic acid group and 12 occurred in the sulfasalazine group. The actuarial relapse rate at 12 months was 20 percent in the 5-aminosalicylic acid group and 24 percent in the sulfasalazine group; at 24 months, these rates were 37 and 43 percent, respectively. The actuarial relapse curves of the two groups were very similar. The relapse severity was also similar between the two groups. These results show that the authors proposed schedule of maintenance treatment with high-dose 5-aminosalicylic acid enemas is effective in subjects with rectosigmoiditis. This form of intermittent therapy may therefore be proposed for maintaining remission in patients who are refractory to oral and/or rectal treatment with sulfasalazine and steroids or who are intolerant or allergic to sulfasalazine. Treatment with 5-aminosalicylic acid enemas for seven days each month can also constitute an alternative for patients who favor the intermittent schedule over the classic continuous regimen of oral administrations.

General and cancer specific mortality of a population based cohort of patients with inflammatory bowel disease: the Florence Study.

BACKGROUND: A population based epidemiological study identified all the patients diagnosed with ulcerative colitis (UC) or Crohn's disease (CD) resident in the Florence area in the period 1978-1992. AIMS: To assess the mortality of unselected patients with inflammatory bowel disease (IBD) in a Mediterranean country. METHODS: Overall, 920 patients (689 UC and 231 CD) were followed until death or end of follow up (31 December 1996). Information on vital status was available for all except eight patients (0.9%); 70 deaths were identified (23 in patients with CD and 47 in patients with UC). Expected deaths were estimated on the basis of five year age group, gender, and calendar year national mortality rates. Standardised mortality ratios (SMR) and 95% confidence intervals were calculated. RESULTS: General mortality was significantly lower than expected in UC (SMR 0.6; 95% confidence interval 0.4 to 0.8), due to a reduced number of cardiovascular and, possibly, smoking related deaths. Cancers of the respiratory tract were significantly reduced in UC but tended to be increased in patients with CD. These latter patients had not only an increased cancer mortality but also a 40% increased risk of dying for all causes already evident in the first five year follow up period and persisting thereafter. In contrast, in patients with UC, SMRs were initially very low but tended to increase steadily over the follow up period. Gastrointestinal deaths were particularly increased in patients with CD, but only moderately in those with UC. Overall, there was some evidence of a twofold increased mortality for colorectal cancer, the risk being highest for rectal cancers in patients with UC. A non-significant excess of deaths due to haemolymphopoietic malignancies and suicides was also observed. CONCLUSIONS: This study, the first in a Mediterranean country, supports the existence of two divergent mortality patterns for patients with UC and CD, possibly explained by differences in smoking habits and by a greater severity of CD.

Spondyloarthritis in patients with ulcerative colitis.

BACKGROUND: Extraintestinal manifestations can complicate the course of ulcerative colitis and can influence the prognosis. AIMS: Sixty-eight patients of the metropolitan area of Florence with ulcerative colitis in clinical and endoscopic remission were evaluated to establish the presence of spondyloarthritis. PATIENTS AND METHODS: Each patient was studied through clinical and radiological evaluations to assess the presence of joint involvement. RESULTS: We found signs of spondyloarthritis in 19 patients (27.9%). Four of them had a classic ankylosing spondylitis (5.8%) and in 3 of them the aplotype HLA B27 was present. Sacroileitis was found in 9 (13.2%) patients (monolateral in 5 cases and bilateral in 4). Six patients (8.8%) showed an unclassifiable form of arthritis, fulfilling the Amor criteria. In 13 of 19 patients with spondyloarthritis, we found a pancolic extension of disease (68.4%). CONCLUSIONS: The results obtained from our series of ulcerative colitis patients reveal a lower proportion of cases of spondyloarthritis than that found in other Italian studies. We are planning further investigations on a larger population to better assess the prevalence of spondyloarthritis in ulcerative colitis patients.

Divergent patterns of total and cancer mortality in ulcerative colitis and Crohn's disease patients: the Florence IBD study 1978-2001.

BACKGROUND AND AIMS: Two divergent patterns of mortality for smoking related diseases in ulcerative colitis and Crohn's disease patients were suggested in a previous population based study in Florence, Italy. Long term follow up (median 15 years) was completed to re-evaluate mortality in this Mediterranean cohort. PATIENTS AND METHODS: Overall, 920 patients with inflammatory bowel disease were followed until December 2001 or death, with seven patients (0.8%) lost to follow up. A total of 14 040 person years were available for analysis; 118 deaths were observed (81/689 in ulcerative colitis and 37/231 in Crohn's disease). Expected deaths were estimated using age, sex, and calendar specific national and local mortality rates; standardised mortality ratios (SMR) and 95% confidence interval (CI) were calculated. RESULTS: Among Crohn's disease patients, mortality was strongly increased for gastrointestinal diseases (SMR 4.49 (95% CI 1.80-9.25)), all cancers (SMR 2.10 (95% CI 1.22-3.36)), and lung cancer (SMR 4.00 (95% CI 1.60-8.24)), leading to a significant 50% excess total mortality. Ulcerative colitis patients showed a significantly reduced total mortality because of lower cardiovascular (SMR 0.67 (95% CI 0.45-0.95)) and lung cancer (SMR 0.32 (95% CI 0.07-0.95)) mortality. No significant excess for colorectal cancer mortality was evident in this extended follow up. CONCLUSIONS: These clearly divergent patterns of mortality correlate with documented differences in smoking habits between Crohn's disease and ulcerative colitis patients. Family doctors and gastroenterologists should consider stopping cigarette smoking a specific priority for Crohn's disease patients; the latter should be offered free participation in structured programmes for smoking cessation, with the aim of reducing smoking related excess mortality. Overall, no evidence of an increased mortality for large bowel cancer emerged in this series.

Epidemiology of inflammatory bowel disease over a 10-year period in Florence (1978-1987).

The epidemiology of inflammatory bowel disease (IBD) in southern Europe is still not well-known. Sporadic reports have suggested a lower incidence and a milder course of the disease in Italy, but conclusive data are still lacking. To shed light on this issue, we conducted a retrospective study of IBD incidence (from January 1978 to December 1987) in the metropolitan area of Florence (650,000 inhabitants). We also estimated IBD prevalence at December 31, 1987. Our study included both in-patients and out-patients referred to the Gastroenterological and Surgical Departments of the area. The diagnosis was based on well-established clinical, endoscopical, radiological, histological and surgical criteria. Overall, nine-hundred IBD patients were identified, but only 359 (195 males, 164 females) met the eligibility criteria for inclusion in the incidence study (area of residence and period of diagnosis); of these, 263 had ulcerative colitis (UC), 96 had Crohn's disease (CD), and 6 had IBD. The average incidence rate of CD was 1.5/100,000 per year while its prevalence was 17.3/100,000. The average incidence rate of UC was 4.0/100,000 per year and the prevalence was 49.6/100,000. Both the incidence and the prevalence rates for UC and CD were higher in males than in females. This retrospective, hospital-based study shows that, in this area, the incidence rate of IBD has steadily increased over the period considered. Further studies specifically focused on risk factors are needed.

Intermittent versus continuous 5-aminosalicylic acid treatment for maintaining remission in ulcerative colitis.

We performed a 12-month clinical trial to compare the relative effectiveness of an intermittent 5-ASA regimen and a continuous 5-ASA regimen for the maintenance treatment of patients with ulcerative colitis in remission. Fifty patients with ulcerative colitis in remission for a minimum period of 1 month participated in the study. Twenty five patients received an intermittent treatment with 5-ASA tablets (2.4 g for the first week of each month) and 25 received a continuous treatment with tablets (1.6 g each day). Patients were assessed clinically every two months and endoscopically every 6 months. Our results show that the two treatments were equally effective. The relapse-free rates at 12 months were 71% in patients receiving the intermittent treatment and 66% in patients given the continuous treatment. This difference is not statically significant. Further studies are needed to assess whether the intermittent regimen can be an alternative to life-long treatment in patients who have maintained remission for a long period of time.

5-Aminosalicylic acid in pregnancy: clinical report.

Ulcerative colitis (UC) is a disease condition which typically affects young people; pregnancy is therefore frequent in women with this disease. 5-aminosalicylic acid (5-ASA) is known to be efficacious in maintaining remission of UC, but its safety in pregnancy has not yet been established. In the present study, the safety of 5-ASA was assessed in 16 women with UC (mean age: 31 years, range 25-35) who had a total of 19 pregnancies over the period from 1988 to 1992. All the patients were in clinical remission of UC at the beginning of pregnancy and were receiving a regular maintenance therapy with 5-ASA (ASACOL tablets, 1.2 g/day). During pregnancy, 4 women had a clinical relapse requiring treatment with higher doses of 5-ASA and, in some cases, with steroids. Our observations confirm that the treatment with 5-ASA does not affect the course of pregnancy nor does it damage the fetus, but it can protect from recurrences of UC.