Aaron Brzezinski

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

ObjectiveRecent 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.MethodsPatients 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.ResultsThirty-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).ConclusionsUC 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.

The effect of folic acid supplementation on the risk for cancer or dysplasia in ulcerative colitis

BACKGROUND & AIMS Two case-control studies have shown that folate may protect against neoplasia in ulcerative colitis. This historical cohort study was performed to better define this association. METHODS The records of 98 patients with ulcerative colitis who had disease proximal to the splenic flexure for at least 8 years were reviewed. Documented folate use of at least 6 months was deemed a positive exposure. RESULTS Of the patients, 29.6% developed neoplasia and 40.2% took folate supplements. The adjusted relative risk (RR) of neoplasia for patients taking folate was 0.72 (95% confidence interval [CI], 0.28-1.83). The dose of folate varied with the risk of neoplasia (RR, 0.54 for 1.0 mg folate; RR, 0.76 for 0.4 mg folate in a multivitamin compared with patients taking no folate). Folate use also varied with the degree of dysplasia (RR for cancer, 0.45; RR for high-grade dysplasia, 0.52; RR for low-grade dysplasia, 0.75 compared with patients with no dysplasia) (P = 0.08). CONCLUSIONS Although not statistically significant, the RR for folate supplementation on the risk of neoplasia is < 1 and shows a dose-response effect, consistent with previous studies. Daily folate supplementation may protect against the development of neoplasia in ulcerative colitis.

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.

Defining complex contributions of NOD2/CARD15 gene mutations, age at onset, and tobacco use on Crohn's disease phenotypes

BackgroundMultiple factors, particularly IBD family history, tobacco use, age at diagnosis and recently, NOD2 mutant genotypes may influence Crohns disease (CD) heterogeneity. MethodsWe performed a multicenter retrospective record analysis of 275 unrelated patients with CD. Age at diagnosis, IBD family history, Jewish ethnicity, tobacco use at diagnosis, surgical history, disease site and clinical behavior were correlated with genotypes for NOD2 mutations, and all risk factors were assessed for independent influence on outcomes of disease site, behavior and surgery free survival. ResultsRisk of ileal disease was increased for CD patients with two NOD2 mutations (Odds Ratio, O.R. 10.1), a smoking history (O.R. 2.25 per pack per day at diagnosis) or a younger age at diagnosis (O.R. 0.97 per each increased year). Presence of ileal disease (O.R. 4.8) and carrying one or two NOD2 mutations (O.R. 1.9 and 3.5, respectively) were independent risk factors for stricturing or non-perianal fistulizing behavior. Ileal disease, youthful onset and smoking at diagnosis (but not NOD2 mutations) were risk factors for early surgery. ConclusionsCarrying two NOD2 mutations predicts youthful onset, ileal disease involvement, and development of stricturing or non-perianal fistulizing complications. Smoking and early onset independently influence ileal site and time to surgery.

Modified Pouchitis Disease Activity Index A Simplified Approach to the Diagnosis of Pouchitis

AbstractPURPOSE: Pouchitis is the most common complication of ileal pouch-anal anastomosis for ulcerative colitis. Our previous study suggested that symptoms alone are not reliable for the diagnosis of pouchitis. The most commonly used diagnostic instrument is the 18-point pouchitis disease activity index consisting of three principal component scores: symptom, endoscopy, and histology. Despite its popularity, the pouchitis disease activity index has mainly been a research tool because of costs of endoscopy (especially with histology), complexity in calculation, and time delay in determining histology scores. It is not known whether pouch endoscopy without biopsy can reliably diagnose pouchitis in symptomatic patients. The aim of the present study was to determine whether omitting histologic evaluation from the pouchitis disease activity index significantly affects the sensitivity and specificity of diagnostic criteria for pouchitis. METHODS: Ulcerative colitis patients with an ileal pouch-anal anastomosis and symptoms suggestive of pouchitis were evaluated. Patients with chronic refractory pouchitis and Crohn’s disease were excluded. Patients with pouchitis disease activity index scores of seven or more were diagnosed as having pouchitis. Different diagnostic criteria were compared on the basis of the pouchitis disease activity index component scores. Nonparametric receiver-operating-characteristic curves were used to measure proposed pouchitis scores’ diagnostic accuracy compared with diagnosis from the pouchitis disease activity index. The receiver-operating-characteristic area under the curve measured how much these diagnostic strategies differed from each other. RESULTS: Fifty-eight consecutive symptomatic patients were enrolled; 32 (55 percent) patients were diagnosed with pouchitis. With the use of the pouchitis disease activity index as a criterion standard, the use of only symptom and endoscopy scores (modified pouchitis disease activity index) produced an area under the curve of 0.995. Establishing a cut-point of five or more for diseased patients resulted in a sensitivity equal to 97 percent and specificity equal to 100 percent. CONCLUSIONS: Diagnosis based on the modified pouchitis disease activity index offers similar sensitivity and specificity when compared with the pouchitis disease activity index for patients with acute or acute relapsing pouchitis. Omission of endoscopic biopsy and histology from the standard pouchitis disease activity index would simplify pouchitis diagnostic criteria, reduce the cost of diagnosis, and avoid delay associated with determining histology score, while providing equivalent sensitivity and specificity.

Irritable pouch syndrome: a new category of diagnosis for symptomatic patients with ileal pouch-anal anastomosis

OBJECTIVE: Pouchitis often is diagnosed based on symptoms alone. However, increased stool frequency, urgency, and abdominal pain could be due to a condition resembling irritable bowel syndrome. This study was designed to assess the etiology of bowel symptoms using the Pouchitis Disease Activity Index (PDAI). METHODS: Symptoms, endoscopy, and histology were assessed in 61 consecutive symptomatic patients with ulcerative colitis after ileal pouch–anal anastomosis. Pouchitis was defined as a PDAI score of 7, cuffitis was defined as endoscopic and histological inflammation of the rectal cuff and no inflammation of the pouch, and irritable pouch syndrome (IPS) was defined as symptoms with a PDAI of 7 and the absence of cuffitis. RESULTS: Thirty-one patients (50.8%) had pouchitis, four (6.5%) had cuffitis, and 26 (42.6%) had IPS. Demographics were similar in the three groups. Increased stool frequency, urgency, and abdominal cramps were the most common symptoms in the three groups. Rectal bleeding was seen only in cuffitis ( p 0.001). No patient in the three groups had fever. Twenty-seven patients (87.1%) with pouchitis responded to a 2-wk course of ciprofloxacin or metronidazole with a reduction in PDAI scores of 3. All four patients with cuffitis responded to topical hydrocortisone or mesalamine with a reduction in the PDAI symptom component score of 1. Twelve patients with IPS (46.2%) responded to antidiarrheal, anticholinergic, and/or antidepressant therapies with a reduction in the PDAI symptom component score of 1, whereas the remaining patients had persistent symptoms despite therapy. CONCLUSIONS: A substantial number of symptomatic patients after ileal pouch–anal anastomosis do not meet the diagnostic criteria for either pouchitis or cuffitis and have been classified as having IPS. There is an overlap of symptoms among patients with pouchitis, cuffitis, and IPS, and endoscopic evaluation can differentiate among these groups. Distinction between these three groups has therapeutic implications. (Am J Gastroenterol 2002;97:972–977.

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.

Differentiating risk factors for acute and chronic pouchitis

BACKGROUND & AIMS Pouchitis is the most common complication of ileal pouch anal anastomosis in patients with ulcerative colitis. In some cases the inflammation becomes chronic and requires long-term medical therapy. The clinical course and medical therapy are different between acute pouchitis and chronic pouchitis. The aim of this study was to determine if there are predictors of risk for acute vs. chronic pouchitis. METHODS Patients with acute pouchitis (N = 40) and patients with chronic pouchitis (N = 40) were matched with a control group who never had pouchitis (N = 40). Data were collected for multiple pre-, peri-, and postoperative factors and follow-up telephone calls were performed. Case-control univariable analyses and multivariate logistic regression were used to measure the association between covariates and pouchitis. RESULTS Multivariate logistic regression showed that extensive colonic disease (odds ratio [OR], 2.99; P = .045 for acute pouchitis; and OR, 4.61; P = .010 for chronic pouchitis) and extraintestinal manifestations (OR, 2.88; P = .037 for acute pouchitis; and OR, 2.69; P = .047 for chronic pouchitis) were associated with both acute and chronic pouchitis. Postoperative nonsteroidal anti-inflammatory drug (NSAID) use was associated with chronic pouchitis, but less so with acute pouchitis. Patients with fulminant colitis as an indication for surgery had a decreased risk for developing chronic pouchitis (OR, 0.22; P = .036), but no such association was seen for acute pouchitis. CONCLUSIONS Extensive colonic disease and preoperative extraintestinal manifestations are associated with increased risk for both acute and chronic pouchitis. Fulminant colitis leading to colectomy is protective from development of chronic pouchitis. Postoperative use of NSAIDS is a risk factor for chronic pouchitis and possibly for acute pouchitis, and thus should be discouraged for patients who undergo ileal pouch anal anastomosis.

Treatment of Rectal Cuff Inflammation (Cuffitis) in Patients with Ulcerative Colitis Following Restorative Proctocolectomy and Ileal Pouch-Anal Anastomosis

BACKGROUND:Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the treatment of choice in the majority of patients with ulcerative colitis (UC) who require surgery. To ease the construction of the IPAA and improve functional outcome by minimizing sphincter related stretch injury, a stapling technique is being commonly used in the pouch-anal anastomosis. Despite its advantages, the procedure normally leaves a 1–2 cm of anal transitional zone or rectal cuff, which is susceptible to recurrence of residual UC or cuffitis. Cuffitis can cause symptoms mimicking pouchitis.AIM:To conduct an open-labeled trial of topical mesalamine in patients with cuffitis.METHODS:We treated 14 consecutive patients with cuffitis by giving mesalamine suppositories 500 mg b.i.d. (mean 3.2 months, range 1–9 months). The Cuffitis Activity Index (adapted from the Pouchitis Disease Activity Index) scores and improvement in symptoms of bloody bowel movements and arthralgias were measured as primary and secondary outcomes.RESULTS:All patients had surgery for medically refractory UC. There were significant reductions in the total Cuffitis Activity Index scores after the therapy (11.93 ± 3.17 vs 6.21 ± 3.19, p < 0.001). Symptom (3.24 ± 1.28 vs 1.79 ± 1.31), endoscopy (3.14 ± 1.29 vs 1.00 ± 1.52), and histology (4.93 ± 1.77 vs 3.57 ± 1.39) scores each were significantly reduced (p < 0.05). Ninety-two percent of patients with bloody bowel movements and 70% of patients with arthralgias improved after the therapy. No systemic or topical adverse effects were reported.CONCLUSION:Topical mesalamine appears well tolerated and effective in treating patients with cuffitis, with improvement in symptom as well as endoscopic and histologic inflammation.

An Oral Supplement Enriched With Fish Oil, Soluble Fiber, and Antioxidants for Corticosteroid Sparing in Ulcerative Colitis: A Randomized, Controlled Trial

BACKGROUND & AIMS N-3 fatty acids from fish oil, antioxidants, and short-chain fatty acids (SCFAs) produced during the fermentation of soluble fiber may attenuate inflammation associated with ulcerative colitis (UC). We assessed the efficacy of a nutritionally balanced oral supplement enriched with fish oil, fructooligosaccharides, gum arabic, vitamin E, vitamin C, and selenium on disease activity and medication use in adults with mild to moderate UC. METHODS A total of 121 patients with UC and a disease activity index (DAI) from 3-9 on a 12-point scale were block randomized for extent of disease and smoking status. In addition to their usual diet, patients consumed 18 oz of the oral supplement or a carbohydrate-based placebo formula each day for 6 months. Clinical and histologic responses were assessed at 3 and 6 months or at the final visit. A change in average prednisone use between groups was tested by using a linear mixed-effects model. RESULTS Eighty-six patients completed the study. Baseline characteristics were not different between groups except for a higher total DAI score in the oral supplement group (7.3 +/- 1.3; n = 36) compared with the placebo group (6.2 +/- 2.0; n = 50) ( P < .05). Both groups showed significant and similar degree of improvement at 6 months in DAI (-2.5 for oral supplement and -2.8 for placebo) and histologic index (-1.9 for oral supplement vs. -2.0 for placebo). Both intent-to-treat and completed patients given oral supplement had a significantly greater rate of decrease in the dose of prednisone required to control clinical symptoms over 6 months as compared with the placebo group ( P < .001). CONCLUSIONS The improvement in clinical response combined with a decreased requirement for corticosteroids suggest that this enriched oral supplement can be a useful adjuvant therapy in patients with UC.