Disease activity was assessed in 10 (five males and five females) ulcerative colitis patients through the following parameters: clinical, laboratory, sigmoidoscopic and histological. Protein metabolism was also assessed with 15N-glycine and urinary ammonia as end product. Only one patient had exacerbation of the disease two months after the study started. This patient presented in the beginning of the study protein synthesis and breakdown of 4.51 and 3.47 g protein/kg/day, respectively, values higher than all other patients, showing an hypermetabolic state, suggesting an increase of the disease activity. However, this increase was not detected by others indicators and indexes utilised. These data allow to suggest the hypothesis that protein metabolism predicts precociously the exacerbation of disease activity in ulcerative colitis patients.
To determine if specific anticolon antibodies bound to colonic mucosa occur in ulcerative colitis, we obtained surgical specimens of colon from five patients with ulcerative colitis, one patient with diverticulitis, and three control subjects with carcinoma. Two specimens of ileum and cecum were also obtained from patients with Crohn ileocolitis. Tissue was homogenized and washed and bound Ig was eluted by citrate buffer, pH 3.2. Concentrated eluates of all specimens from patients with ulcerative colitis reacted with antisera to κ and γ and not with antisera to α and μ chains. Corresponding eluates from all other specimens did not react with these antisera, but did react with antialbumin. The presence of IgG in ulcerative colitis eluates was also determined by immunoelectrophoresis, immunocoprecipitation, and affinity chromatography with antisera against human IgG.
BACKGROUND/AIMS: Regional differences in the biology of the colonic epithelium may determine the extent of involvement by ulcerative colitis. Novel monoclonal antibodies (MAbs) were used in this study to investigate regional heterogeneity in the colonic mucosa. METHODS: MAbs generated using a method of tolerisation against common antigens in the proximal colon and distal colon were used for immunoperoxidase staining, comparative histochemistry, immunoblotting, and slot-blot analysis. RESULTS: The colon specific MAbs 5F1 (IgG3) and 6G4 (IgM) stained goblet cell contents throughout the normal distal colon but staining was markedly reduced in the proximal colon (p < 0.0001). In the distal colon of patients with ulcerative colitis, whether quiescent or actively inflamed, reactivity was reduced compared with controls (p < 0.05, p < 0.001 respectively). By contrast, an overall increase in staining was seen in the uninflamed proximal colon in ulcerative colitis compared with controls (p < 0.02). Comparative staining with high iron diamine and biochemical analyses indicated that MAb 6G4 was reactive with mucin bearing sulphate or O-acetylated sialic acid groups, or both. CONCLUSIONS: Regional differences in the staining characteristics of normal colonic mucin have been shown using novel monoclonal antibodies. The pattern of mucin expression throughout the colon in ulcerative colitis is altered even in the absence of histological changes.
BACKGROUND: The aetiology and pathophysiology of ulcerative colitis remains unclear; however, there is increasing recognition of the critical role of inflammatory cytokines in the pathogenesis of this disease. Among these, tumour necrosis factor alpha (TNF alpha) seems to play an important role. AIM: To study the effects of an engineered human monoclonal antibody to TNF alpha (CDP571) in the treatment of idiopathic ulcerative colitis in the cottontop tamarin. METHODS: Six cottontop tamarins with confirmed ulcerative colitis received repeated doses of CDP571. Progression of disease was assessed by measuring both body weight and rectal biopsy pathology. RESULTS: All animals showed a rapid improvement in clinical condition and rectal biopsy pathology that was maintained following completion of the therapy. CONCLUSION: These studies indicate the efficacy of selective antibody therapy to TNF alpha for the treatment of ulcerative colitis in a primate and suggest that similar therapy in human could be of value.
OBJECTIVE: Restorative proctocolectomy for mucosal ulcerative colitis is well established. However, the effect of age on physiologic sphincter parameters is poorly understood. Our objective was to determine whether age at the time of restorative proctocolectomy correlates with physiologic changes. SUMMARY BACKGROUND DATA: In the approximately 20 years during which restorative proctocolectomy has been performed for ulcerative colitis, the indications have changed. Initially, the procedure was recommended only in patients under approximately 50 years. However, the procedure has been considered in older patients because of the increasing age of our population, the increasing frequency of recognition of patients during the "second peak" of mucosal ulcerative colitis, and the decreasing morbidity rates, due to the learning curve and to newer techniques, such as double-stapling. Few authors have presented data analyzing the effects of this operation in older patients. METHODS: One hundred twenty-two patients who had undergone a two-stage restorative proctocolectomy for mucosal ulcerative colitis were divided into three groups according to age: group I (>60 years), 11 men, 6 women; group II (40-60 years), 29 men, 18 women; and group III (<40 years) 29 men...
OBJECTIVE: This study determined predictive factors for postoperative complications and outcome after ileal pouch-anal anastomosis in patients with ulcerative colitis and primary sclerosing cholangitis. SUMMARY BACKGROUND DATA: Patients with ulcerative colitis and primary sclerosing cholangitis treated by colectomy and ileostomy are at high risk of troublesome bleeding from peristomal varices. METHODS: Postoperative complications and outcome were assessed in 40 patients with ulcerative colitis and sclerosing cholangitis who received an ileal pouch-anal anastomosis between January 1981 and February 1990. RESULTS: Immediate postoperative and remote ileoanal anastomosis-related complications were high but related directly to the severity of liver disease. No patient had perianastomotic anal bleeding. CONCLUSIONS: In patients with both ulcerative colitis and primary sclerosing cholangitis, ileal pouch-anal anastomosis is safe and is not associated with perianastomotic bleeding.
To determine the factors responsible for ulcerative colitis relapse a cohort of 92 patients (18 to 78 years, 50 men) with clinically inactive disease have been followed for over 48 weeks. At 12 weekly intervals patients were asked, by means of standardised questionnaires, about infections, compliance with maintenance medication, new drug treatment, dietary changes, episodes of non-bloody diarrhoea, life stresses, and feelings of anxiety and depression. Thirty five patients (38%) relapsed (median interval 17 weeks, range three to 46 weeks). Patients who relapsed had a higher previous relapse rate than non-relapsers (p less than 0.001) and a shorter time from previous relapse to trial entry (p less than 0.05). Other clinical characteristics were equally matched in the two groups. Between and within group comparisons revealed that upper respiratory tract symptoms, antibiotic ingestion, analgesic intake, diarrhoeal episodes and stressful life events were no more common in the four weeks before relapse than before routine attendance. Anxiety and depression ratings were also similar in the two groups. The timing of ulcerative colitis relapse showed a clear seasonal pattern with 26 patients relapsing from August to January and only nine from January to July (p less than 0.001). In addition...
Serum anticolon antibody and in vitro anti-colon antibody production by peripheral blood and mucosal lymphocytes was investigated in patients with ulcerative colitis. The frequency of serum anticolon antibody was 71% in 41 patients with ulcerative colitis, estimated by enzyme linked immunosorbent assay (ELISA) using isolated rat colon epithelial cells. This finding confirms our previous report on the frequency of serum anticolon antibody detected by flow cytometry analysis. The estimated frequencies of IgG anticolon antibody secreting cells were 1.5-12.5/10(6) cells in the colonic mucosa and 0.1-0.5/10(6) cells in peripheral blood, from patients with ulcerative colitis when Epstein-Barr virus (EBV) was used as a B cell polyclonal activator. Poisson analysis of limiting dilution culture showed that about one per 140 IgG cells in the colonic mucosa synthesised anticolon antibody. Two monoclonal IgG antibodies were obtained from EBV transformed anticolon antibody secreting cells by limiting dilution method. One reacted with goblet cells in the intestine, and the other reacted mainly with colonic epithelial cells. These results suggest that heterogeneous anticolon antibodies are present in patients with ulcerative colitis and that colonic mucosa may be the main source of anticolon antibody. Local autoimmune reaction might have an important role in causing the inflammation of colonic mucosa in this disease.
We have examined the age at onset of both ulcerative colitis and colitis-associated colorectal cancer in 100 patients seen at Mount Sinai Hospital between 1959 and 1988. There were 85 patients with extensive colitis and 15 with left sided colitis. There was a strong direct correlation between the age at onset of ulcerative colitis and age at diagnosis of cancer (p less than 0.0001); this correlation was found both in patients with extensive colitis (p less than 0.0001) and in those with left sided colitis (p less than 0.005). Patients with left sided colitis developed both their colitis and their cancers about a decade later than did those with extensive disease, but the mean duration of colitis before diagnosis of cancer was virtually the same (about 21 years) in both groups, irrespective of the age at onset of disease.
From 1976 to 1989 a total of 66 patients with longstanding ulcerative colitis were entered in a colonoscopic surveillance programme in order to detect dysplasia. Thirty patients had extensive or total ulcerative colitis and 36 left sided colitis. The median duration of the disease at the end of the follow up was 15.0 years. Altogether 182 colonoscopies (2.8 per patient), each involving approximately 20 biopsies from different sites of the colon, were performed. In the total or extensive colitis group, five patients had low grade and one patient had high grade dysplasia. In the left sided colitis group, three patients had low grade dysplasia. In three patients low grade dysplasia was detected in a macroscopic lesion or mass of colonic mucosa. Sixty per cent of the dysplasia specimens were from the right colon. The incidence of dysplasia was higher in patients with extensive colitis and increased with the duration of the disease. None of the patients have so far developed colorectal carcinoma. Our results indicate that a colonoscopic surveillance programme is a safe alternative to prophylactic colectomy in longstanding ulcerative colitis.
The assessment of disease severity in ulcerative colitis depends mainly on subjective variables, and an objective method of assessing mucosal inflammation is needed. Determination of the synthetic phase of the cell cycle is an accurate expression of inflammatory activity in the colonic mucosa. The aim of the study was to find out if the proliferative index or the synthetic phase (S phase) of the colonic mucosa of patients with ulcerative colitis, as evaluated by DNA flow cytometry, is a reliable and reproducible marker of disease activity. Sixty consecutive patients with ulcerative colitis of different degrees of activity were entered into the study and submitted to colonoscopy plus multiple rectal biopsies. Disease severity was defined for each patient by means of a clinical, endoscopic, and histological score. Flow cytometry was used to calculate the proliferative index and the S phase of the cell cycle. A statistically significant correlation (p < 0.001) was found between all indices of severity. It is suggested that flow cytometric evaluation of the cell cycle in the rectal mucosa may be an efficient method of assessing severity of disease and efficacy of medical treatment in ulcerative colitis.
BACKGROUND--An increasing number of patients with severe or refractory ulcerative colitis involving only the rectum and sigmoid colon are being offered restorative proctocolectomy with ileal reservoir but very few data are available concerning the outcome for these patients. AIM--This study was designed to compare the outcome of ileal pouch procedures for distal ulcerative colitis with procedures performed for more extensive disease. PATIENTS--A consecutive series of 177 patients undergoing restorative proctocolectomy for ulcerative colitis between January 1984 and December 1994. METHODS--Data were collected prospectively in a dedicated ileal pouch database and included demographic details, indication for surgery, surgical procedures performed, early (< 30 days) and late morbidity, functional outcome, and histopathology. RESULTS--There was no mortality in the series. The incidence and range of early morbidity (< 30 days) and the functional outcome (daytime stool frequency, nocturnal frequency, and the incidence of incontinence) were similar for all groups. Log rank analysis of Kaplan-Meier estimates showed no significant difference between groups in the likelihood of developing pouchitis (p > 0.2). CONCLUSIONS--Patients undergoing restorative proctocolectomy for distal colitis experience a similar outcome to patients with more extensive disease. These data refute the hypothesis that pouchitis is more common in patients with total colitis.
BACKGROUND: The mechanisms underlying the frequent development of colorectal carcinomas in patients with ulcerative colitis are still unknown. AIMS: To evaluate whether mucosal necrosis and regeneration act as enhancing or promoting factors in colorectal tumorigenesis, development of multiple colorectal tumours was studied in a murine model of ulcerative colitis with azoxymethane pretreatment. METHODS: Periods of chronic ulcerative colitis in mice were induced by three repeated administrations of 3% dextran sulphate sodium subsequent to a single azoxymethane pretreatment, to give conditions similar to the clinically observed active and remission phases. RESULTS: In the chronic colitis group with carcinogen exposure, multiple mucosal tumours (10.5/mouse) developed in the colorectum. This occurred primarily on the left side of the large intestine or transverse colon, the sites of the most severe colitic injury. The observed lesions were high grade dysplasias and invasive adenocarcinomas. Increased cell proliferation was evidenced by high uptake of bromodeoxyuridine, and increased activities of thymidylate synthetase and thymidine kinase. No tumours were induced in the control groups with azoxymethane pretreatment or chronic colitis alone. CONCLUSIONS: Repeated mucosal erosion with necrosis and regeneration is critical for the development of colorectal tumours in this experimental colitis system.
Fifteen patients with ulcerative colitis and 11 patients with ulcerative proctitis have been observed and studied for periods ranging from one to 15 years. It is suggested that the clinical course of the two disorders is quite distinct. Further, while the serum immunoglobulins were within normal limits in ulcerative proctitis, significant increases in the serum α2-, β-, and γ-globulins and in the IgA and IgG concentrations were found in ulcerative colitis. Despite total colectomy for ulcerative colitis, the serum IgG and IgA concentration remained high and even after subsequent rectal resection the relative IgA concentration continued to increase. The significance of these findings is discussed.
This paper compares the mortality of 525 men admitted to U.S. Army hospitals in 1944 with ulcerative colitis compared with 518 controls matched for age, race, and rank. The excess mortality in the ulcerative colitis group as compared with the control group was due to approximately equal proportions of deaths from ulcerative colitis (2·9%) and cancer of the caecum, colon, and rectum (3·2%). The mortality from ulcerative colitis occurred mainly in the first and immediately subsequent years after diagnosis while most of the deaths from cancer occurred in later years. A striking correlation is shown between bad prognosis and the extent of radiological involvement of the colon in 1944.
OBJECTIVE--To determine whether azathioprine can prevent relapse in ulcerative colitis. DESIGN--One year placebo controlled double blind trial of withdrawal or continuation of azathioprine. SETTING--Outpatient clinics of five hospitals. SUBJECTS--79 patients with ulcerative colitis who had been taking azathioprine for six months or more. Patients in full remission for two months or more (67), and patients with chronic low grade or corticosteroid dependent disease (12) were randomised separately. 33 patients in remission received azathioprine and 34 placebo; five patients with chronic stable disease received azathioprine and seven placebo. MAIN OUTCOME MEASURE--Rate of relapse. Relapse was defined as worsening of symptoms or sigmoidoscopic appearance. RESULTS--For the remission group the one year rate of relapse was 36% (12/33) for patients continuing azathioprine and 59% (20/34) for those taking placebo (hazard rate ratio 0.5, 95% confidence interval 0.25 to 1.0). For the subgroup of 54 patients in long term remission (greater than six months before entry to trial) benefit was still evident, with a 31% (8/26) rate of relapse with azathioprine and 61% (17/28) with placebo (p less than 0.01). For the small group of patients with chronic stable colitis (six were corticosteroid dependent and six had low grade symptoms) no benefit was found from continued azathioprine therapy. Adverse events were minimal. CONCLUSIONS--Azathioprine maintenance treatment in ulcerative colitis is beneficial for at least two years if patients have achieved remission while taking the drug. Demonstration of the relapse preventing properties of azathioprine has implications for a large number of patients with troublesome ulcerative colitis...
We have analyzed K-ras mutations and p53 alterations in 39 tumor and nontumor samples taken from nine patients with longstanding ulcerative colitis and colorectal carcinoma. Two of nine invasive carcinomas contained a K-ras mutation. By a combination of immunohistochemistry and single-strand conformation polymorphism analysis, p53 alterations were found in three of nine carcinomas. Five of 13 dysplastic lesions harbored a mutated K-ras gene, even in the absence of detectable changes in associated invasive tumors. One single focus of dysplastic mucosa harbored concomitant K-ras and p53 gene alterations. In two patients, a K-ras mutation was detected in epithelial lesions considered to be devoid of malignant potential (villous regeneration, active colitis). Our results indicate that: 1) the prevalence of K-ras and p53 genetic alterations found in ulcerative colitis-associated colonic carcinomas appears to be lower than in sporadic carcinomas; 2) K-ras mutations can be detected in dysplasia, villous regeneration, and active colitis and affect a subpopulation of the cells composing the lesions; 3) diverse genetic alterations can be detected in the same patient and the dysplastic lesions can exhibit a different genotype than the carcinomas; and 4) at least part of active colitis and villous regeneration lesions should be considered as preneoplastic in ulcerative colitis.
We determined the ionic composition of faecal fluid from 13 patients with Crohn's disease limited to the colon, 10 with diffuse ulcerative colitis, and eight with ulcerative proctitis. The Crohn's and colitis groups had similar proportions of colon surface involved radiographically and similar 24 hour faecal weights. However, Crohn's patients' faecal fluid had arithmetically lower mean sodium and statistically lower mean chloride (34.8 mmol/l +/- 16.2 SD vs. 53.1 mmol/l +/- 23.1 SD) and higher potassium (49.2 mmol/l +/- 20.2 SD vs. 33.0 mmol/l +/- 13.8 SD) concentrations (p less than 0.05 for each) and much higher osmolality (487.1 mOsmol/kg +/- 87.1 SD vs. 341.1 mOsmol/kg +/- 88.9 SD, p less than 0.001). Separation of these patients using the faecal osmotic gap agreed with the clinical classification in 86% of cases. The diarrhoea of proctitis patients had a nearly normal ionic composition which was clearly distinguishable from that of diffuse colitis. These results suggest differences in the composition and perhaps the pathogenesis of the diarrhoea of Crohn's and ulcerative colitis. The composition of fluid may prove a useful, non-invasive method for classifying patients with inflammatory bowel disease and, in ulcerative colitis...
Rectal biopsies were collected from control subjects, patients with ulcerative colitis both active and quiescent, and from patients with Crohn's disease, both with and without rectal involvement, as judged by histological assessment. Tissue homogenates were assayed for neutrophil (vitamin B12 binding protein, myeloperoxidase, lysozyme) and lymphocyte (5' nucleotidase) selective markers. Patients with acute but not those with quiescent colitis had striking increases of the neutrophil markers. Neither patient group with ulcerative colitis showed a change in the lymphocyte marker enzyme activity. Patients with Crohn's disease involving the rectum showed significant, but less marked, increases in the activity of the neutrophil markers that were found in active ulcerative colitis. Patients with Crohn's disease, not involving the rectum, showed normal or reduced levels of neutrophil markers. Patients with Crohn's disease, both those with and without rectal involvement, had increased activities of the lymphocyte selective marker. This distinguishes this inflammatory response from that of ulcerative colitis and provides further biochemical evidence of abnormalities in apparently uninvolved mucosa from Crohn's patients.
A prospective surveillance programme for patients with longstanding (> = 8 years), extensive (> = splenic flexure) ulcerative colitis was undertaken between 1978 and 1990. It comprised annual colonoscopy with pancolonic biopsy. One hundred and sixty patients were entered into the programme and had 739 colonoscopies (4.6 colonoscopies per patient; 709 patient years follow up). Eight eight per cent of examinations reached the right colon. There was no procedure related death. One Dukes's A cancer was detected. Forty one patients (25%) defaulted. Of these 25 remain well; 13 are unaccounted for, and one died from colonic cancer. One patient had colectomy for medical reasons, and another died of carcinoma of the pancreas. Retrospectively an additional 16 eligible patients were identified who had not been recruited. Of these, 14 remain well, two are unaccounted for. None developed colonic cancer. Four patients refused colonoscopy. All remain well. Over the same period seven other cases of colonic cancer were found in association with ulcerative colitis, two in patients who had erroneously been diagnosed as having only proctitis and were therefore not entered into the programme, but were found at operation to have total colitis, one in a patient with colitis of seven years duration...