Chromoendoscopy Is More Effective Than Standard Colonoscopy in Detecting Dysplasia During Long-term Surveillance of Patients With Colitis.

BACKGROUND & AIMS: Patients with colitis have an increased risk of colorectal cancer, compared with persons without colitis. Many studies have shown chromoendoscopy (CE) to be superior to standard methods of detecting dysplasia in patients with colitis at index examination. We performed a prospective, longitudinal study to compare standard colonoscopy vs CE in detecting dysplasia in patients with inflammatory bowel diseases in a surveillance program. METHODS: We analyzed data from 68 patients (44 men, 24 women) diagnosed with ulcerative colitis (n = 55) or Crohn's disease (n = 13) at Mount Sinai Medical Center from September 2005 through October 2011. The patients were followed from June 2006 through October 2011 (median, 27.8 months); each patient was analyzed by random biopsy, targeted white light examination (WLE), and CE. Specimens were reviewed by a single blinded pathologist. The 3 methods were compared by using the generalized estimating equations method, and the odds ratios (ORs) for detection of dysplasia were calculated (primary outcome). Time to colectomy was analyzed by using the Cox model. RESULTS: In the 208 examinations conducted, 44 dysplastic lesions were identified in 24 patients; 6 were detected by random biopsy, 11 by WLE, and 27 by CE. Ten patients were referred for colectomy, and no carcinomas were found. At any time during the study period, CE (OR, 5.4; 95% confidence interval [CI], 2.9-9.9) and targeted WLE (OR, 2.3; 95% CI, 1.0-5.3) were more likely than random biopsy analysis to detect dysplasia. CE was superior to WLE (OR, 2.4; 95% CI, 1.4-4.0). Patients identified as positive for dysplasia were more likely to need colectomy (hazard ratio, 12.1; 95% CI, 3.2-46.2). CONCLUSIONS: In a prospective study of 68 patients with inflammatory bowel diseases, CE was superior to random biopsy or WLE analyses in detecting dysplasia in patients with colitis during an almost 28-month period. A negative result from CE examination was the best indicator of a dysplasia-free outcome, whereas a positive result was associated with earlier referral for colectomy.

Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis.

BACKGROUND & AIMS: In the Active Ulcerative Colitis Trial (ACT)-1 and ACT-2, patients with ulcerative colitis treated with infliximab were more likely than those given placebo to have a clinical response, undergo remission, and have mucosal healing. We investigated the association between early improvement (based on endoscopy) and subsequent clinical outcome. METHODS: Patients underwent endoscopic evaluations at weeks 0, 8, 30, and 54 (ACT-1 only), and were categorized into 4 subgroups by week 8 (Mayo endoscopy subscore, 0-3). The association of week 8 endoscopy subscores, subsequent colectomy risk, symptoms and corticosteroid use outcomes were analyzed. Mucosal healing was defined as a Mayo endoscopy subscore of 0 (normal) or 1 (mild). RESULTS: Infliximab-treated patients with lower week 8 endoscopy subscores were less likely to progress to colectomy through 54 weeks of follow-up evaluation (P=.0004). This trend was not observed among patients given placebo (P=.47). Patients with lower endoscopy subscores achieved better symptomatic and corticosteroid use outcomes at weeks 30 and 54 (P<.0001, infliximab; P<.01, placebo). Among patients who achieved clinical response at week 8, trends in subsequent clinical outcomes by week 8 endoscopy subscores were generally consistent with that for the overall patient population; no trends were observed among patients who achieved clinical remission. CONCLUSIONS: The degree of mucosal healing after 8 weeks of infliximab was correlated with improved clinical outcomes including colectomy. Similar trends were observed for all outcomes except colectomy among the subgroup with clinical response at week 8. The degree of mucosal healing at week 8 among those in clinical remission did not predict subsequent disease course.

The effect of intravenous cyclosporine on rates of colonic surgery in hospitalized patients with severe Crohn's colitis.

BACKGROUND: The role of intravenous (IV) cyclosporine in severe Crohn's colitis (CC) is poorly studied. AIM: Our primary aim was to determine the in-hospital colonic resection rate in patients with severe CC who received IV cyclosporine, and the potential predictors of resection among these patients. METHODS: An inpatient pharmacy query of all patients who received IV cyclosporine at Mount Sinai Medical Center for 12.5 years after January 1, 1996 was reviewed. Patients with CC or indeterminate colitis favoring Crohn's were included and their medical records were reviewed. Subsequent need for colonic surgery was assessed. A Kaplan-Meier plot with log-rank testing was performed to determine the rate of colonic surgery avoidance. Forward stepwise logistic regression was performed to determine independent predictors of surgery. RESULTS: Forty-eight patients met our inclusion criteria. Prior thiopurine and anti-tumor necrosis factor (anti-TNF) use was 85% and 69%, respectively. The median follow-up time was 12 months (range, 1 to 60 mo). 12.5% of patients required colonic resection during their admission for IV cyclosporine. Anti-TNF use in the 4 weeks preceding IV cyclosporine was the only predictor of surgery in this setting (P=0.05). The cumulative colonic surgery avoidance rate was 72±13% at 6 months and 59±15% at 12 months. CONCLUSIONS: The use of IV cyclosporine resulted in a low rate of in-hospitalization colonic surgery among CC patients with severe disease, the majority of whom previously failed anti-TNFs and thiopurines.

Evaluation of 22 genetic variants with Crohn's disease risk in the Ashkenazi Jewish population: a case-control study.

BACKGROUND: Crohn's disease (CD) has the highest prevalence among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Caucasian populations (NJ). We evaluated a set of well-established CD-susceptibility variants to determine if they can explain the increased CD risk in the AJ population. METHODS: We recruited 369 AJ CD patients and 503 AJ controls, genotyped 22 single nucleotide polymorphisms (SNPs) at or near 10 CD-associated genes, NOD2, IL23R, IRGM, ATG16L1, PTGER4, NKX2-3, IL12B, PTPN2, TNFSF15 and STAT3, and assessed their association with CD status. We generated genetic scores based on the risk allele count alone and the risk allele count weighed by the effect size, and evaluated their predictive value. RESULTS: Three NOD2 SNPs, two IL23R SNPs, and one SNP each at IRGM and PTGER4 were independently associated with CD risk. Carriage of 7 or more copies of these risk alleles or the weighted genetic risk score of 7 or greater correctly classified 92% (allelic count score) and 83% (weighted score) of the controls; however, only 29% and 47% of the cases were identified as having the disease, respectively. This cutoff was associated with a >4-fold increased disease risk (p < 10e-16). CONCLUSIONS: CD-associated genetic risks were similar to those reported in NJ population and are unlikely to explain the excess prevalence of the disease in AJ individuals. These results support the existence of novel, yet unidentified, genetic variants unique to this population. Understanding of ethnic and racial differences in disease susceptibility may help unravel the pathogenesis of CD leading to new personalized diagnostic and therapeutic approaches.

Cyclosporine is safe and effective in patients with severe ulcerative colitis.

BACKGROUND: Cyclosporine (CSA) is effective in the short-term for severe, steroid refractory ulcerative colitis; but its use has been limited by concerns about safety and colectomy-sparing rates. The aim of this study was to assess the long-term colectomy-sparing effects and safety of CSA in patients hospitalized for ulcerative colitis. METHODS: Review of the patients who underwent intravenous CSA for ulcerative colitis between 1989 and 2003. RESULTS: A total of 71 patients with severe ulcerative colitis were treated with IV CSA. The median length of follow-up was 1.5 years (mean=3 y) (range 1 mo to 14 y) (IQR 0.6 to 4.6). Eighty-five percent (60/71) of patients responded to IV CSA and were discharged on oral CSA. Of these 60 patients, 26 were transitioned from CSA to 6MP. Of the 26 patients who were transitioned from CSA to 6MP, only 1 patient (4%) ultimately required colectomy; whereas colectomy was carried out in 76% (26/34) of the patients who were not transitioned from CSA to 6MP. Only concomitant 6MP therapy was associated with a reduced risk of colectomy (OR 0.01, 95% CI 0.001, 0.09, P<0.0001) on long-term follow-up in this group. Cumulative colectomy rates for the entire cohort were 39% (28/71) at 1 year, 42% (30/71) at 2 years, and 46% (33/71) at 5 years. Side effects were noted in two-thirds of the patients, the majority of which were mild. CONCLUSION: CSA is an effective therapy for severe ulcerative colitis. Long-term efficacy is improved with transition to 6MP. Adverse events with CSA are frequent, but most are mild.

Practice patterns in the use of anti-tumor necrosis factor alpha agents in the management of Crohn's disease: a US national practice survey comparing experts and non-experts.

BACKGROUND: The US Food and Drug Administration currently approves three types of anti-tumor necrosis factor α (anti-TNFα) therapy for treatment of moderate to severe Crohn's disease. There are no guidelines to clarify which of the drugs may be better suited to individual clinical scenarios. AIMS: We gathered national data on the prescribing pattern, comfort levels, and algorithms gastroenterologists use for management of their biologic-requiring Crohn's disease patients. METHODS: An internet survey was mailed to members of the American Gastroenterology Association. Responses were separated into "non-expert" and "expert" physician groups on the basis of whether a practice consisted of >50% of patients with inflammatory bowel disease. We compared experts with non-experts with regard to the use of the three anti-TNF agents, attitudes regarding their relative efficacy, and their experience with adverse events. RESULTS: Of 3,990 eligible gastroenterologists, 473 replied in full (11.9%). Sixty (12.6%) respondents met the criterion for IBD expert physician. Experts were comfortable using both immunomodulators and anti-TNFα therapy. Community physicians were equally comfortable prescribing 6-mercaptopurine, azathioprine, infliximab, and adalimumab, but less comfortable than experts with methotrexate (56 vs. 86%, P<0.05) and certolizumab (68 vs. 89%, P<0.05). Expert physicians were much more likely to have encountered adverse reactions to anti-TNFα therapy. CONCLUSIONS: Our results suggest that experts are more comfortable using a broader array of medical therapy than non-expert physicians. Although both groups had similar concerns regarding side-effects of anti-TNFα therapy, expert physicians were much more likely to have managed a broad range of complications in their patient population.

Colectomy rate comparison after treatment of ulcerative colitis with placebo or infliximab.

BACKGROUND & AIMS: The efficacy of infliximab for treating patients with ulcerative colitis has been established. METHODS: The Active Ulcerative Colitis Trial (ACT)-1 and ACT-2 randomized, double-blind, placebo-controlled studies evaluated infliximab induction and maintenance therapy in moderately to severely active ulcerative colitis. Overall, 728 patients received placebo or infliximab (5 or 10 mg/kg) intravenously at weeks 0, 2, and 6, then every 8 weeks through week 46 (ACT-1) or 22 (ACT-2). Colectomy, hospitalization, and surgery/procedure data through 54 weeks after the first infusion were obtained from ACT-1, ACT-2, and associated data sources. In the prespecified analysis, all data were combined to ascertain time to colectomy. Kaplan-Meier product-limit method was used to estimate the cumulative incidence of colectomy, and log-rank test was used to compare the combined infliximab group and placebo. RESULTS: Eighty-seven percent (630 of 728) of patients had complete colectomy follow-up; 13% (98 of 728) of patients had a median follow-up of 6.2 months. The cumulative incidence of colectomy through 54 weeks was 10% for infliximab and 17% for placebo (P = .02), yielding an absolute risk reduction of 7%. Compared with placebo, fewer ulcerative colitis-related hospitalizations and surgeries/procedures per 100 patient-years of treatment occurred with infliximab therapy: 40 vs 20 (P = .003) and 34 vs 21 (P = .03), respectively. Serious adverse events occurring in infliximab-treated patients included serious infections, tuberculosis, histoplasmosis, listeriosis, and malignancy. CONCLUSIONS: Patients with moderately to severely active ulcerative colitis treated with infliximab were less likely to undergo colectomy through 54 weeks than those receiving placebo.

Rosiglitazone for active ulcerative colitis: a randomized placebo-controlled trial.

BACKGROUND & AIMS: Thiazolidinedione ligands for the gamma subtype of peroxisome proliferator-activated receptors (PPARgamma), widely used to treat type 2 diabetes mellitus, have been proposed as novel therapies for ulcerative colitis (UC). METHODS: This multicenter, randomized, double-blind, placebo-controlled clinical trial compared the efficacy of rosiglitazone (Avandia; GlaxoSmithKline, Philadelphia, PA) 4 mg orally twice daily vs placebo twice daily for 12 weeks in 105 patients with mild to moderately active UC. Disease activity was measured with the Mayo score. The primary end point was clinical response (>/=2-point reduction) at week 12. Clinical remission (Mayo score

Infliximab for induction and maintenance therapy for ulcerative colitis.

BACKGROUND: Infliximab, a chimeric monoclonal antibody directed against tumor necrosis factor alpha, is an established treatment for Crohn's disease but not ulcerative colitis. METHODS: Two randomized, double-blind, placebo-controlled studies--the Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and ACT 2, respectively)--evaluated the efficacy of infliximab for induction and maintenance therapy in adults with ulcerative colitis. In each study, 364 patients with moderate-to-severe active ulcerative colitis despite treatment with concurrent medications received placebo or infliximab (5 mg or 10 mg per kilogram of body weight) intravenously at weeks 0, 2, and 6 and then every eight weeks through week 46 (in ACT 1) or week 22 (in ACT 2). Patients were followed for 54 weeks in ACT 1 and 30 weeks in ACT 2. RESULTS: In ACT 1, 69 percent of patients who received 5 mg of infliximab and 61 percent of those who received 10 mg had a clinical response at week 8, as compared with 37 percent of those who received placebo (P<0.001 for both comparisons with placebo). A response was defined as a decrease in the Mayo score of at least 3 points and at least 30 percent, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute rectal-bleeding subscore of 0 or 1. In ACT 2, 64 percent of patients who received 5 mg of infliximab and 69 percent of those who received 10 mg had a clinical response at week 8, as compared with 29 percent of those who received placebo (P<0.001 for both comparisons with placebo). In both studies, patients who received infliximab were more likely to have a clinical response at week 30 (P< or =0.002 for all comparisons). In ACT 1, more patients who received 5 mg or 10 mg of infliximab had a clinical response at week 54 (45 percent and 44 percent, respectively) than did those who received placebo (20 percent, P<0.001 for both comparisons). CONCLUSIONS: Patients with moderate-to-severe active ulcerative colitis treated with infliximab at weeks 0, 2, and 6 and every eight weeks thereafter were more likely to have a clinical response at weeks 8, 30, and 54 than were those receiving placebo. (ClinicalTrials.gov numbers, NCT00036439 and NCT00096655.)

Screening and surveillance colonoscopy in chronic Crohn's colitis: results of a surveillance program spanning 25 years.

BACKGROUND & AIMS: Since 1980, we have followed 259 patients with chronic Crohn's colitis in a prospective colonoscopic surveillance program. Our initial results through August 1998 showed a 22% chance of developing definite dysplasia or cancer by the fourth surveillance examination. We now update the results of all examinations since September 1998 until April 2005. METHODS: All patients had at least 7 years of Crohn's colitis affecting at least one third of the colon. Patients were recalled every 1 to 2 years or sooner if dysplasia was found. Pathology was classified as normal, dysplasia (indefinite, low-grade [LGD], or high-grade [HGD]), or carcinoma. Lesions were classified as flat, polyp, or mass. RESULTS: A total of 1424 examinations were performed on 259 patients. Ninety percent had extensive colitis. The median age at diagnosis was 22 years (range, 2-61 y), and the median disease duration was 18 years (range, 7-49 y). On screening examination, definite dysplasia or cancer was found in 18 patients (7%). Thirteen had LGD, 2 had HGD, and 3 had cancer. On surveillance examinations, a first finding of definite dysplasia or cancer was found in an additional 30 patients (14%). Twenty-two had LGD, 4 had HGD, and 4 had cancer. The cumulative risk of detecting an initial finding of any definite dysplasia or cancer after a negative screening colonoscopy was 25% by the 10th surveillance examination. The cumulative risk of detecting an initial finding of flat HGD or cancer after a negative screening colonoscopy was 7% by the ninth surveillance examination. CONCLUSIONS: Periodic surveillance colonoscopy should be part of the routine management of chronic extensive Crohn's colitis.

Cyclosporine and infliximab as rescue therapy for each other in patients with steroid-refractory ulcerative colitis.

BACKGROUND & AIMS: In patients with severe corticosteroid-refractory ulcerative colitis, cyclosporine or infliximab may be added in an effort to induce remission. If the patient then fails either of these drugs, it is unknown whether success can be achieved by using the other agent. The aim of this study was to assess outcomes of using cyclosporine after failure of infliximab, and vice versa. METHODS: We retrospectively reviewed the charts of 19 patients with corticosteroid-refractory ulcerative colitis who received either infliximab after failed cyclosporine or cyclosporine after failed infliximab. Acute salvage therapy was defined as having received the alternate drug within 4 weeks of discontinuing the first agent. RESULTS: Ten patients received infliximab after failing cyclosporine; 9 patients received cyclosporine after failing infliximab. Four patients (40%) in the infliximab-salvage group achieved remission, as did 3 (33%) in the cyclosporine-salvage group. Remission lasted a mean of 10.4 months (range, 4.4-17.03 mo) and 28.5 months (range, 5.0-41.5 mo), respectively. Severe adverse events included one patient who developed sepsis and died after receiving infliximab salvage. One patient who received cyclosporine salvage developed herpetic esophagitis, and another patient who received cyclosporine salvage developed pancreatitis and bacteremia. CONCLUSIONS: In patients with severe corticosteroid-refractory ulcerative colitis who fail treatment with either cyclosporine or infliximab, remission rates using acute salvage therapy by crossing over to the other drug occur in approximately one third of patients and have limited duration. Serious adverse events occurred in 16%, including 1 death, suggesting that the risks of acute salvage therapy may outweigh the benefits.

Relapses of inflammatory bowel disease during pregnancy: in-hospital management and birth outcomes.

BACKGROUND: There are few studies that describe the medical treatment and colitis response rates among patients with a severe relapse of inflammatory bowel disease (IBD) during pregnancy, and few studies of the effect of such a relapse on birth outcomes in these patients. OBJECTIVES: To describe the treatment and response rates of severe colitis in pregnancy, and to assess the effects of a severe relapse of colitis during pregnancy on birth outcomes. METHODS: We performed a case control study of pregnant patients with IBD hospitalized for a disease relapse at two large treatment centers between 1989 and 2001. Details of management of disease relapse and maternal and fetal outcomes were recorded. RESULTS: Eighteen patients (11 ulcerative colitis, 6 Crohn's disease, 1 indeterminate colitis), mean age 28.6 yr (range 19-38) formed the study group; 41 age-matched pregnant IBD patients without disease relapse formed the control group. Study patients were hospitalized at a mean of 15.9-wk gestation (range 8-35) for a mean of 10.4 days (range 3-31). All 18 patients received IV hydrocortisone (mean dose 199 mg/day) and 7 patients (39%) either continued taking or were commenced on immunomodulators: IV cyclosporine (5 patients) and azathioprine/6-MP (3 patients). Fifteen patients (83%) had a clinical response to these medical treatments, 3 patients required colectomy. There were significant differences between study and control groups in gestation period (35.0 wk vs 38.7 wk, respectively, P= 0.0001) and birth weight (2,001 g vs 3,018 g, respectively, P < 0.0001). CONCLUSIONS: Treatment with IV hydrocortisone and IV cyclosporine appears effective at inducing remission of colitis but their use must continue to be confined to severely ill patients being treated at specialized centers. Severe relapses of colitis during pregnancy increase the risk of preterm birth and low birth weight.

Adverse events associated with the use of cyclosporine in patients with inflammatory bowel disease.

BACKGROUND: Intravenous cyclosporine (i.v. CsA) is an effective therapy for patients with inflammatory bowel disease (IBD). However, data regarding its adverse events in these patients are limited. METHODS: A retrospective chart review of the initial 111 consecutive patients with IBD treated with i.v. CsA followed by a predetermined duration of oral therapy. RESULTS: One hundred eleven patients (64 UC, 47 CD; mean age 33 yr, range 16-68) received i.v. CsA at 4 mg/kg/day, then oral CsA at 8 mg/kg/day, with dose adjustment based on serum creatinine. The mean treatment duration was 9.3 months (range 1 wk to 34 months). Major adverse events occurred in 17 (15.3%) patients. Nephrotoxicity (serum creatinine > or = 1.4 mg/dL [123 micromol/L] or a rise by at least 33% over baseline not responding to dose adjustment) sufficiently severe to warrant discontinuation of therapy occurred in 6 (5.4%) patients. Serious infection occurred in 7 (6.3%) patients, seizures in 4 (3.6%) patients, anaphylaxis in 1 (0.9%) patient, and death in 2 (1.8%) patients. Minor adverse events (transient effects with complete resolution either spontaneously or with dose adjustment) comprised: paresthesias (51%), hypomagnesemia (42%), hypertension (39%), hypertrichosis (27%), headache (23%), minor nephrotoxicity (defined as above but with restoration of normal serum creatinine with dose adjustment; 19% of patients), abnormal liver function tests (19%), minor infections (15%), hyperkalemia (13%), and gingival swelling (4%). CONCLUSIONS: In our initial experience, limited duration CsA therapy was frequently associated with adverse events although the majority of these were minor and responded to dose adjustment. Although not all severe adverse events can be clearly attributed to CsA use alone, its high incidence suggests that vigorous monitoring by experienced clinicians at tertiary care centers may be required.

Chromoendoscopy-targeted biopsies are superior to standard colonoscopic surveillance for detecting dysplasia in inflammatory bowel disease patients: a prospective endoscopic trial.

OBJECTIVES: Patients with extensive, longstanding chronic ulcerative or Crohn's colitis face greater risks of developing colorectal cancer. Current standard surveillance relies on detecting dysplasia using random sampling at colonoscopy but may fail to detect dysplasia in many patients. Dye spraying techniques have been reported to aid in detecting otherwise subtle mucosal abnormalities in the setting of colitis. We prospectively compared dye-spray technique using methylene blue to standard colonoscopic surveillance in detecting dysplasia. METHODS: One hundred fifteen patients were referred to the Chromoendoscopy Study Group and prospectively screened for the study. One hundred two (64 M, 38 F) (79 UC 23 CC) patients meeting the inclusion criteria were enrolled. Following a standard bowel preparation, each patient was examined using standard office endoscopic equipment by three methods: (a) standard surveillance colonoscopy with four random biopsies every 10 cm (for a total of at least 32 samples); (b) a targeted biopsy protocol; and finally (c) methylene blue (0.01%) dye spray was segmentally applied throughout the colon and any pit-pattern abnormality or lesion rendered visible by the dye spray was targeted and biopsied. Each patient had a single examination, which included two passes of the colonoscope. Specimens were reviewed in a blinded fashion by a single gastrointestinal pathologist. The three methods were then compared with each patient serving as his or her own control. RESULTS: Targeted biopsies with dye spray revealed significantly more dysplasia (16 patients with low grade and 1 patient with high grade) than random biopsies (3 patients with low-grade dysplasia) (P= 0.001) and more than targeted nondye spray (8 patients with low-grade and 1 patient with high-grade dysplasia) (P= 0.057). Targeted biopsies with and without dye spray detected dysplasia in 20 patients compared with 3 using Method (a) (P= 0.0002, two-tailed exact McNemar's Test). There were no adverse events. CONCLUSIONS: Colonoscopic surveillance of chronic colitis patients using methylene blue dye-spray targeted biopsies results in improved dysplasia yield compared to conventional random and targeted biopsy methods. Accordingly, this technique warrants incorporation into clinical practice in this setting and consideration as a standard of care for these patients. The value of multiple random biopsies as a surveillance technique should be revisited.

Pouch-ouch.

PURPOSE OF REVIEW: For patients who require colectomy, the ileal pouch anal anastomosis operation has alleviated the need for permanent ileostomy and has improved associated self-esteem issues. The most common complication of this surgery, however, is pouchitis. This review highlights the most recent research in the pathophysiology, risk factors, diagnosis and management of pouchitis, and pouch surveillance for neoplasia in patients who had ulcerative colitis. RECENT FINDINGS: Markers of inflammation, including fecal lactoferrin and mucosal cytokines, have been reported as useful in differentiating between irritable pouch syndrome and pouchitis. Numerous risk factors for the development of pouchitis have been identified. They include the presence of perinuclear antinuclear cytoplasmic antibodies, steroid use prior to colectomy, dysplasia as the indication for colectomy, the presence of extraintestinal manifestations, and an elevated platelet count. Therapy for acute pouchitis remains a short course of antibiotics. For chronic pouchitis, studies found success with rifaximin, tinidazole, and oral budesonide. Cancer in the residual rectal mucosa, in the ileal mucosa, and in pouch polyps occurs frequently enough to warrant surveillance. SUMMARY: Risk factors for the development of pouchitis should be discussed with patients. Less invasive diagnostic strategies have been proposed and antibiotics are still the mainstay of therapy.

Anti-interleukin-12 antibody for active Crohn's disease.

BACKGROUND: Crohn's disease is associated with excess cytokine activity mediated by type 1 helper T (Th1) cells. Interleukin-12 is a key cytokine that initiates Th1-mediated inflammatory responses. METHODS: This double-blind trial evaluated the safety and efficacy of a human monoclonal antibody against interleukin-12 (anti-interleukin-12) in 79 patients with active Crohn's disease. Patients were randomly assigned to receive seven weekly subcutaneous injections of 1 mg or 3 mg of anti-interleukin-12 per kilogram of body weight or placebo, with either a four-week interval between the first and second injection (Cohort 1) or no interruption between the two injections (Cohort 2). Safety was the primary end point, and the rates of clinical response (defined by a reduction in the score for the Crohn's Disease Activity Index [CDAI] of at least 100 points) and remission (defined by a CDAI score of 150 or less) were secondary end points. RESULTS: Seven weeks of uninterrupted treatment with 3 mg of anti-interleukin-12 per kilogram resulted in higher response rates than did placebo administration (75 percent vs. 25 percent, P=0.03). At 18 weeks of follow-up, the difference in response rates was no longer significant (69 percent vs. 25 percent, P=0.08). Differences in remission rates between the group given 3 mg of anti-interleukin-12 per kilogram and the placebo group in Cohort 2 were not significant at either the end of treatment or the end of follow-up (38 percent and 0 percent, respectively, at both times; P=0.07). There were no significant differences in response rates among the groups in Cohort 1. The rates of adverse events among patients receiving anti-interleukin-12 were similar to those among patients given placebo, except for a higher rate of local reactions at injection sites in the former group. Decreases in the secretion of interleukin-12, interferon-gamma, and tumor necrosis factor alpha by mononuclear cells of the colonic lamina propria accompanied clinical improvement in patients receiving anti-interleukin-12. CONCLUSIONS: Treatment with a monoclonal antibody against interleukin-12 may induce clinical responses and remissions in patients with active Crohn's disease. This treatment is associated with decreases in Th1-mediated inflammatory cytokines at the site of disease.

Rifaximin for the treatment of active pouchitis: a randomized, double-blind, placebo-controlled pilot study.

BACKGROUND: The efficacy of the nonabsorbable antibiotic rifaximin in patients with active acute or chronic pouchitis is unknown. METHODS: We performed a placebo-controlled pilot trial to evaluate the efficacy and safety of rifaximin in patients with active pouchitis. Eighteen patients with active pouchitis were randomized to receive oral rifaximin 400 mg or placebo 3 times daily for 4 weeks. Active pouchitis was defined as a total Pouchitis Disease Activity Index (PDAI) score = 7 points. Clinical remission was defined as a PDAI score <7 points and a decrease in the baseline PDAI score = 3 points. The primary analysis was clinical remission at week 4. RESULTS: Eight patients were randomized to rifaximin and 10 patients were randomized to placebo. One patient in the placebo group did not have a post-baseline efficacy evaluation and was excluded from the efficacy analysis. Two of 8 patients (25%) treated with rifaximin were in clinical remission at week 4 compared to 0 of 9 patients (0%) treated with placebo (P = 0.2059). None of 8 patients in the rifaximin group withdrew from the trial prior to week 4. Two of 9 patients in the placebo group withdrew prior to week 4 due to lack of efficacy and were categorized as treatment failures. CONCLUSIONS: Clinical remission occurred more frequently in patients treated with rifaximin 400 mg 3 times daily but the difference was not significant in this pilot study. A larger trial would be required to determine if rifaximin is effective for the treatment of active pouchitis. Rifaximin was well tolerated.

Consensus conference: Colorectal cancer screening and surveillance in inflammatory bowel disease.

The idiopathic inflammatory bowel diseases, ulcerative colitis and Crohn's colitis, are associated with an increased risk for developing colorectal cancer. To reduce colorectal cancer mortality in inflammatory bowel disease, most patients and their physicians choose to follow a program of surveillance colonoscopy in an attempt to detect early neoplastic lesions at a curable stage. Colectomy is typically reserved for patients whose biopsy findings are indicative of heightened cancer risk based on interpretation by pathologists. Despite the absence of prospective controlled clinical trials to formally evaluate the benefits, risks, and costs of this approach, enough circumstantial evidence has accrued to warrant its widespread adoption in practice. Nevertheless, no standardized guidelines have yet been set forth to guide the gastroenterologist in performing surveillance. A panel of international experts was assembled to develop consensus recommendations for the performance of surveillance. The findings are presented herein.

Optimizing therapy in patients with pancolitis.

Pancolitis affects approximately 20% to 40% of the total ulcerative colitis population and remains a therapeutic challenge for clinicians. Practitioners must focus on pancolitis when evaluating a patient for ulcerative colitis, because pancolitis is associated with more severe and fulminant disease and a higher rate of colorectal cancer and colectomy. It is imperative for clinicians to be knowledgeable in the clinical course, medications, and appropriate manner to induce and maintain clinical remission to prevent serious sequelae of the disease. The purpose of this article is to provide a review of the treatment of pancolitis for general gastroenterologists, because medical management decisions have life-long effects for this subgroup of patients.

6-Mercaptopurine is effective in Crohn's disease without concomitant steroids.

BACKGROUND: 6-Mercaptopurine (6-MP) has shown efficacy in the treatment of Crohn's disease when used in conjunction with corticosteroids. Sparse literature to date suggests that 6-MP is effective when used without steroids. We therefore studied the efficacy of 6-MP in corticosteroid-naive Crohn's patients. METHODS: We conducted a retrospective chart review of 24 patients who were treated with 6-MP but had never received any form of steroid treatment at any time. 6-MP efficacy was assessed with serial modified Harvey-Bradshaw scores. In addition to overall response, data were also analyzed according to the indication for treating with 6-MP (disease activity, fistulae, or both). The time to relapse and the treatments required were also analyzed. RESULTS: Overall, remission or significant improvement was seen in 20 patients (83% of original group). Seven patients (29%) achieved complete remission; another 13 patients (54%) demonstrated significant clinical improvement. By indication, 89% of patients treated for activity, 50% of patients treated for activity and fistula, and 100% of patients treated for fistula alone showed response. Drug effect required a median of 5.7 months to occur (for all patients: range, 1.7-37.9 months). Thirteen of the twenty patients who improved or remitted on 6-MP eventually relapsed, usually due to stopping 6-MP, at a median of 13.8 months (range, 0.9-57.8). Relapse was less frequent if patients continued 6-MP. Treatment of relapses required only antibiotics, and/or restarting 6-MP (or increasing the dose) in most patients. CONCLUSIONS: 6-MP is an effective medication for use in steroid-naive patients and is likely to be effective in patients who have received steroids in the past but are not currently receiving them. Relapses occur despite continued therapy, but are often easily treated, and do not require initiating steroids.