The impact of ulcerative colitis on the long-term outcome of patients with primary sclerosing cholangitis.

BACKGROUND: The impact of ulcerative colitis (UC) on the outcome of primary sclerosing cholangitis (PSC) outcome remains unclear. AIM: To investigate whether the presence of UC is associated with a worse clinical of associated PSC. METHODS: A total of 222 patients with PSC (167 with UC and 55 without UC) seen and followed at a single centre from 1985 to 2011 were included. Clinical and demographic variables were obtained and patients were followed until the date of their last clinic visit. RESULTS: The median age at presentation of PSC with associated UC was 38 vs. 47 years without UC (P < 0.001). At presentation, median serum bilirubin (2.1 vs. 4.5, P < 0.001) and the Mayo PSC Risk Score (0.95 vs. 1.69, P < 0.001) were lower in those with UC vs. those without UC. A total of 55 of 167 (32.9%) patients with PSC-UC developed colon neoplasia in contrast to 1 of the 55 (1.8%) patients with PSC. (P < 0.001) On proportional hazards analysis, UC (hazard ratio (HR) = 0.90 [95% confidence interval (CI): 0.60-1.34, P = 0.60] was not associated with death or orthotopic liver transplantation (OLT), when adjusting for gender, Mayo risk score and year of PSC diagnosis; whereas the revised Mayo risk score [HR = 5.08, 95% CI: (2.62-9.86), P < 0.001] was associated with a greater risk of OLT or death. CONCLUSIONS: Primary sclerosing cholangitis often is recognised at an early stage in patients with concurrent ulcerative colitis; ulcerative colitis has no impact on long-term prognosis in terms of liver-related outcomes when adjusted for the severity of liver disease.

The effects of liver transplantation on the clinical course of colitis in ulcerative colitis patients with primary sclerosing cholangitis.

BACKGROUND: The course of ulcerative colitis (UC) following orthotopic liver transplantation (OLT) for primary sclerosing cholangitis (PSC) is unclear. AIM: To investigate the clinical course of UC, before and after OLT for PSC. METHODS: From a historical cohort of 86 patients with PSC-UC who underwent OLT, 77 patients who were followed up at our institution both before and after OLT from 1985 to 2011 were included. RESULTS: Ulcerative colitis was diagnosed in 77 (97.5%) patients before OLT. Nineteen of 77 (24.7%) patients underwent colectomy before OLT. In the other 58 patients, the course of UC after OLT when compared to the last 5 years before OLT was quiescent in 48 patients (82.8%) while 9/58 (15.5%) of patients underwent colectomy post-OLT. There was a total of 97 colitis flares over a total of 621 years of follow-up from PSC/UC diagnosis to OLT (0.156 flares per patient year) whereas post-OLT, there were 31 flares over a total of 511 years of post-OLT follow-up (0.061 flares per patient year) (P < 0.001). On univariable analysis, the number of UC flares [Odds ratio (OR) 1.52; 95% Confidence interval (1.02-2.27), P = 0.04] and dysplasia [OR 47.00; 95% CI (6.48-340.66), P < 0.001] increased the risk of colectomy following OLT; the use of corticosteroids [OR 0.07; 95% CI (0.01-0.63), P = 0.008] and 5-aminosalicylate [OR 0.18; 95% CI (0.04-0.83), P = 0.04] was protective. CONCLUSIONS: Ulcerative colitis in the presence of primary sclerosing cholangitis remains quiescent, and may improve in most patients after orthotopic liver transplantation.

Collagenous pouchitis.

Collagenous colitis is characterised by watery diarrhoea, normal colonic mucosa on endoscopy, diffuse colitis with surface epithelial injury, and a distinctive thickening of the subepithelial collagen table on histology. Some patients can develop medically refractory collagenous colitis, in which case they may require surgical intervention. This is the first report of collagenous pouchitis in a collagenous colitis patient with proctocolectomy and ileal pouch-anal anastomosis. A patient with medically refractory collagenous colitis who underwent a total proctocolectomy and ileal pouch-anal anastomosis was sequentially evaluated with an endoscopy and histology of the colon, distal small intestine, and ileal pouch. A 58-year-old female had a 10-year history of collagenous colitis before having a total proctocolectomy and ileal pouch-anal anastomosis for medically refractory disease. The histologic features of collagenous colitis were present in all colon and rectum biopsy or resection specimens, but were absent in the distal ileum specimen. The post-operative course was complicated by persistent increase of stool frequency, abdominal cramps, and incontinence. A pouch endoscopy was performed 3 years after ileal pouch-anal anastomosis which showed the histologic features of collagenous colitis in the ileal pouch, collagenous pouchitis, while the pre-pouch neo-terminal ileum had no pathologic changes. After antibiotic therapy, the histologic changes of collagenous pouchitis resolved. This is the first reported case of collagenous pouchitis. Since the abnormal collagen table and its associated features were only present in the pouch and absent in the neo-terminal ileum, and the patient had histologic improvement after antibiotic therapy, it would suggest that faecal stasis and bacterial load may play a role in the pathogenesis.

The impact of ursodeoxycholic acid on cancer, dysplasia and mortality in ulcerative colitis patients with primary sclerosing cholangitis.

BACKGROUND: Colorectal cancer in primary sclerosing cholangitis patients with ulcerative colitis is mostly right-sided where concentrations of carcinogenic secondary bile acids are highest. AIM: To investigate whether ursodeoxycholic acid could be chemopreventive for colorectal cancer. METHODS: A historical cohort study was performed on primary sclerosing cholangitis patients with ulcerative colitis where the 28 patients (cases) who were treated with ursodeoxycholic acid for at least 6 months (mean 3.4 +/- 2.7 years) were compared with the 92 patients (controls) who were not treated with ursodeoxycholic acid. The primary outcomes were colorectal cancer and dysplasia. The secondary outcome was overall mortality. RESULTS: The cumulative incidence of dysplasia or cancer was not significantly different between cases and controls (P = 0.17 by log-rank test). The adjusted relative risk for cases of developing dysplasia or cancer was 0.59 (95% CI 0.26-1.36). The cumulative mortality was significantly different between groups (P = 0.02 by log-rank test). The adjusted relative risk for cases of death was 0.44 (95% CI 0.22-0.90). CONCLUSION: In ulcerative colitis patients with primary sclerosing cholangitis, ursodeoxycholic acid did not reduce the risk of developing cancer or dysplasia. However, ursodeoxycholic acid may reduce mortality.

Maintenance therapy with a probiotic in antibiotic-dependent pouchitis: experience in clinical practice.

BACKGROUND: Management of antibiotic-dependent pouchitis is often challenging. Oral bacteriotherapy with probiotics (such as VSL #3) as maintenance treatment has been shown to be effective in relapsing pouchitis in European trials. However, this agent has not been studied in the US, and its applicability in routine clinical practice has not been evaluated. AIM: To determine compliance and efficacy of probiotic treatment in patients with antibiotic-dependent pouchitis. METHODS: Thirty-one patients with antibiotic-dependent pouchitis were studied. VSL #3 is a patented probiotic preparation of live freeze-dried bacteria. All patients received 2 weeks of ciprofloxacin 500 mg b.d. followed by VSL #3 6 g/day for 8 months. Baseline Pouchitis Disease Activity Index scores were calculated. Patients' symptoms were reassessed at week 3 when VSL #3 therapy was initiated and at the end of the 8-month trial. Some patients underwent repeat pouch endoscopy at the end of the trial. RESULTS: All 31 patients responded to the 2-week ciprofloxacin trial with resolution of symptoms and they were subsequently treated with VSL #3. The mean duration of follow-up was 14.5+/-5.3 months (range: 8-26 months). At the 8-month follow-up, six patients were still on VSL #3 therapy, and the remaining 25 patients had discontinued the therapy due to either recurrence of symptoms while on treatment or development of adverse effects. All six patients who completed the 8-month course with a mean treatment period of 14.3+/-7.2 months (range: 8-26 months) had repeat clinical and endoscopic evaluation as out-patients. At the end of 8 months, these six patients had a mean Pouchitis Disease Activity Index symptom score of 0.33+/-0.52 and a mean Pouchitis Disease Activity Index endoscopy score of 1.83+/-1.72, which was not statistically different from the baseline Pouchitis Disease Activity Index endoscopy score of 2.83+/-1.17 (P=0.27). CONCLUSION: This study was conducted to evaluate bacteriotherapy in routine care. The use of probiotics has been adopted as part of our routine clinical practice with only anecdotal evidence of efficacy. Our review of patient outcome from the treatment placebo showed that only a minority of patients with antibiotic-dependent pouchitis remained on the probiotic therapy and in symptomatic remission after 8 months.

A randomized clinical trial of ciprofloxacin and metronidazole to treat acute pouchitis.

Metronidazole is effective for the treatment of acute pouchitis after ileal pouch-anal anastomosis, but it has not been directly compared with other antibiotics. This randomized clinical trial was designed to compare the effectiveness and side effects of ciprofloxacin and metronidazole for treating acute pouchitis. Acute pouchitis was defined as a score of 7 or higher on the 18-point Pouchitis Disease Activity Index (PDAI) and symptom duration of 4 weeks or less. Sixteen patients were randomized to a 2-week course of ciprofloxacin 1,000 mg/d (n = 7) or metronidazole 20 mg/kg/d (n = 9). Clinical symptoms, endoscopic findings, and histologic features were assessed before and after therapy. Both ciprofloxacin and metronidazole produced a significant reduction in the total PDAI score as well as in the symptom, endoscopy, and histology subscores. Ciprofloxacin lowered the PDAI score from 10.1+/-2.3 to 3.3+/-1.7 (p = 0.0001), whereas metronidazole reduced the PDAI score from 9.7+/-2.3 to 5.8+/-1.7 (p = 0.0002). There was a significantly greater reduction in the ciprofloxacin group than in the metronidazole group in terms of the total PDAI (6.9+/-1.2 versus 3.8+/-1.7; p = 0.002), symptom score (2.4+/-0.9 versus 1.3+/-0.9; p = 0.03), and endoscopic score (3.6+/-1.3 versus 1.9+/-1.5; p = 0.03). None of patients in the ciprofloxacin group experienced adverse effects, whereas three patients in the metronidazole group (33%) developed vomiting, dysgeusia, or transient peripheral neuropathy. Both ciprofloxacin and metronidazole are effective in treating acute pouchitis with significant reduction of the PDAI scores. Ciprofloxacin produces a greater reduction in the PDAI and a greater improvement in symptom and endoscopy scores, and is better tolerated than metronidazole. Ciprofloxacin should be considered as one of the first-line therapies for acute pouchitis.

Endoscopic and histologic evaluation together with symptom assessment are required to diagnose pouchitis.

BACKGROUND & AIMS: Pouchitis often is diagnosed based on symptoms alone. In this study, we evaluate whether symptoms correlate with endoscopic and histologic findings in patients with ulcerative colitis and an ileal pouch-anal anastomosis. METHODS: Symptoms, endoscopy, and histology were assessed in 46 patients using Pouchitis Disease Activity Index (PDAI). Patients were classified as either having pouchitis (PDAI score > or =7; N = 22) or as not having pouchitis (PDAI score <7; N = 24). RESULTS: Patients with pouchitis had significantly higher mean total PDAI scores, symptom scores, endoscopy scores, and histology scores. There was a similar magnitude of contribution of each component score to the total PDAI for the pouchitis group. Of note, 25% of patients with symptoms suggestive of pouchitis did not meet the PDAI diagnostic criteria for pouchitis. In both groups, the correlation coefficients between symptom, endoscopy, and histology scores were near zero (range, -0.26 to 0.20; P > 0.05). CONCLUSIONS: The symptom, endoscopy, and histology scores each contribute to the PDAI and appear to be independent of each other. Symptoms alone do not reliably diagnose pouchitis.

Safety and efficacy of recombinant human interleukin 10 in chronic active Crohn's disease. Crohn's Disease IL-10 Cooperative Study Group.

BACKGROUND & AIMS: Interleukin (IL)-10 is a cytokine with potent anti-inflammatory properties. We investigated the safety and efficacy of different doses of human recombinant (rhu)IL-10 in patients with Crohn's disease (CD). METHODS: A prospective, multicenter, double-blind, placebo-controlled study was conducted in 329 therapy-refractory patients with CD. Clinical improvement was defined by a reduction of the Crohn's Disease Activity Index (CDAI) by 100 points or more and clinical remission by a decrease of the CDAI to <150 points. At selected centers, patients underwent ileocolonoscopies and activation of the nuclear factor-kappa B (NF-kappa B) system was assessed in biopsy specimens. RESULTS: Subcutaneous treatment with rhuIL-10 over 28 days induced a fully reversible, dose-dependent decrease in hemoglobin and thrombocyte counts but no clinically significant side effects. No differences in the induction of remission were observed between rhuIL-10 groups (1 microg, 18% [9.6-29.2]; 4 microg, 20% [11.3-32.2]; 8 microg, 20% [11.1-31.8]; 20 microg, 28% [18-40.7]; and placebo, 18% [9.6-29.6]). Clinical improvement was observed in 46% (33.7-59) in the 8-microg/kg rhuIL-10 group in comparison with 27% (17-39.6) in patients taking placebo. Responders to rhuIL-10 showed inhibition of NF-kappaB p65 activation in contrast to nonresponders. CONCLUSIONS: Up to 8 microg/kg of rhuIL-10 was well tolerated. A tendency toward clinical improvement but not remission was observed in the 8-microg/kg dose group. Further studies should delineate which subgroups of patients with CD benefit from rhuIL-10 therapy.

Can colectomy cure immune thrombocytopenic purpura in a patient with ulcerative colitis?

The association between ulcerative colitis (UC) and immune thrombocytopenic purpura (ITP) has been suggested by sporadic case reports. Prior reports have focused on the role of medical therapy and/or splenectomy for control of concurrent ITP and UC. We report a case of a patient with UC and ITP who was poorly controlled on maximal medical therapy for these two disorders and underwent a colectomy that cured both diseases.

Intestinal adenocarcinoma in Crohn's disease: a report of 30 cases with a focus on coexisting dysplasia.

There are relatively few reports that detail the types of intestinal adenocarcinoma complicating Crohn's disease and examine associated epithelial dysplasia. We determined the prevalence, grade, and type of dysplasia found adjacent to and distant from Crohn's-related adenocarcinomas. Thirty cases of resected Crohn's-related adenocarcinoma were reviewed, and histologic type, degree of differentiation, TNM stage, and the presence or absence, grade, and location of dysplasia were recorded. Most of the patients were male (70%). The median ages at diagnosis of Crohn's disease and adenocarcinoma were 34 and 49 years, respectively. The extent of Crohn's disease included ileocolitis in 21 patients, only colonic disease in six, and only small bowel disease in three. In most cases (67%), carcinoma was found incidentally at surgery. All carcinomas arose in areas involved by Crohn's disease. Eight (27%) adenocarcinomas arose in the small bowel, and 22 (73%) arose in the colon, including two in out-of-circuit rectums. Most carcinomas (63%) were poorly differentiated. Dysplasia was found adjacent to the carcinoma in 26 (87%) cases. Of the colorectal carcinomas, 19 (86%) had adjacent dysplasia, and nine (41%) had distant dysplasia. In conclusion, most cases of Crohn's-related intestinal adenocarcinoma have dysplasia in adjacent mucosa, and 41% of those arising in the colorectum have distant dysplasia, supporting a dysplasia-carcinoma sequence in Crohn's disease.

The risk for cancer or dysplasia in ulcerative colitis patients with primary sclerosing cholangitis.

OBJECTIVES: Recent studies have implicated primary sclerosing cholangitis (PSC) as a risk factor for colorectal cancer (CRC) in ulcerative colitis (UC). Our study was designed to define both the risk and the risk factors for CRC or dysplasia in a large UC cohort with PSC. METHODS: Patients with UC and PSC were compared with a random sample of UC controls without PSC. Patients were analyzed from the inception of disease until an outcome or censor. RESULTS: Thirty-three (25%) of 132 UC patients with PSC developed CRC or dysplasia compared with 11 (5.6%) of 196 controls (adjusted relative risk 3.15, 95% confidence interval 1.37-7.27). Possible risk factors were chronic disease activity and lack of folate supplementation. Of 17 CRCs in the PSC group, 76% occurred proximal to the splenic flexure and 35% presented at an advanced stage, compared with one of five (20%) CRCs in controls being proximal and none being advanced. Six (4.5%) PSC patients, and no controls, died of CRC (p < 0.01). CONCLUSIONS: UC patients with PSC are at increased risk of developing CRC or dysplasia. Chronically active disease may be a risk factor, whereas folate could have a protective effect. CRCs associated with PSC are more likely to be proximal, to be diagnosed at a more advanced stage, and to be fatal.

Evaluation of the usefulness of testing for p53 mutations in colorectal cancer surveillance for ulcerative colitis.

OBJECTIVE: Immunohistochemical staining for p53 suppressor gene mutations is sensitive and, therefore, has potential for use as a complementary test for dysplasia to improve ulcerative colitis (UC) cancer surveillance program performance. METHODS: A cohort of 95 patients with long standing pan-UC enrolled in a surveillance program was studied. Archival colonic biopsy specimens were stained for p53 mutations and clinical information was obtained from medical records. RESULTS: The 37 patients who developed p53 mutations were significantly more likely to develop dysplasia or cancer (relative risk [RR] 4.53, 95% confidence interval [CI] 2.16-9.48). The p53 mutations developed approximately 8 months before low grade dysplasia, 26 months before high grade dysplasia, and 38 months before cancer. Three of seven cancer patients with p53 mutations had Dukes' stage C or D, whereas only one of five cancer patients without p53 mutations had Dukes' C or D; all three patients who died from metastatic cancer had p53 mutations (three of 37 vs 0 of 58, p < 0.03). Folic acid supplementation had a small, significant protective effect for p53 mutations (RR 0.97, CI 0.94-1.00). CONCLUSION: p53 Mutations 1) are associated with, and likely precede, dysplasia and cancer, 2) are associated with cancer-related mortality, and 3) may possibly be prevented by folic acid supplementation.

Mesalamine for prophylaxis of small bowel Crohn's disease recurrence.

Mesalamine has been studied extensively as a therapeutic option in patients with Crohn's disease. Endoscopic follow-up of patients resected for ileal Crohn's disease has shown that, in the absence of treatment, postoperative recurrence occurs in approximately 70% to 90% of patients within 1 year of the operation. Recurrence requires further surgical intervention in approximately half of patients within 10 years. Therapeutic strategies aimed at preventing recurrence are essential to the management of patients with Crohn's disease. This article offers a critical evaluation of results from clinical studies of mesalamine for prevention of recurrence in small bowel Crohn's disease.

Sarcoidosis presenting as granulomatous colitis.

Sarcoidosis presenting solely as a granulomatous colitis is rare and appears identical to Crohn's disease. A 56-yr-old woman developed a Crohn's-like illness, which remitted after 5-ASA therapy. Two months later, she developed fever, adenopathy, muscle weakness, and peripheral neuropathy. A diagnosis of sarcoidosis was made after an extensive search for an infectious or rheumatological cause. This case illustrates the utility of serum angiotensin converting enzyme level in differentiating sarcoidosis from Crohn's disease.