Michael F. Picco

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.

SCENIC International Consensus Statement on Surveillance and Management of Dysplasia in Inflammatory Bowel Disease

Patients with ulcerative colitis or Crohn’s colitis have an increased risk of colorectal cancer (CRC). Most cases are believed to arise from dysplasia, and surveillance colonoscopy therefore is recommended to detect dysplasia. Detection of dysplasia traditionally has relied on both examination of the mucosa with targeted biopsies of visible lesions and extensive random biopsies to identify invisible dysplasia. Current U.S. guidelines recommend obtaining at least 32 random biopsy specimens from all segments of the colon as the foundation of endoscopic surveillance. However, much of the evidence that provides a basis for these recommendations is from older literature, when most dysplasia was diagnosed on random biopsies of colon mucosa. With the advent of video endoscopy and newer endoscopic technologies, investigators now report that most dysplasia discovered in patients with inflammatory bowel disease (IBD) is visible. Such a paradigm shift may have important implications for the surveillance and management of dysplasia. The evolving evidence regarding newer endoscopic methods to detect dysplasia has resulted in variation among guideline recommendations from organizations around the world. We therefore sought to develop unifying consensus recommendations addressing 2 issues: (1) How should surveillance colonoscopy for detection of dysplasia be performed? (2) How should dysplasia identified at colonoscopy be managed?

SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease.

Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut; Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut; Veterans Affairs Palo Alto Healthcare System and Stanford University School of Medicine (affiliate), Palo Alto, California; Division of Gastroenterology, McGill University, Montreal, Quebec, Canada; University of California at San Francisco, Veterans Affairs Medical Center, San Francisco, California; University of Leeds, Leeds, United Kingdom

Tobacco consumption and disease duration are associated with fistulizing and stricturing behaviors in the first 8 years of Crohn's disease

OBJECTIVES:Crohns disease (CD) can be classified by site of involvement and by clinical behavior. Claims for stability of behavior are based on patients who have had surgery, usually within 8 yr of diagnosis. Disease during this period may begin as inflammatory and may evolve into stricturing or fistulizing behavior. Our aim was to determine the influence of genetic and environmental factors on the prevalence of inflammatory behavior among patients who have had CD for <8 yr.METHODS:Disease type (inflammatory, stricturing, or fistulizing), site, and duration were determined in 311 consecutive patients with CD. The analysis was then restricted to those with a disease duration of <8 yr, and influences on the prevalence of inflammatory type disease were compared with those of the complicated type (fistulizing and stricturing), including disease site, family history, Jewish ethnicity, and pack-years of cigarette smoking after diagnosis were determined through univariate and multivariate analyses.RESULTS:The prevalence of inflammatory type disease was 0.63 and 0.3 (p < 0.0001) in patients with a disease duration of <8 yr and ≥8 yr, respectively. Multivariate analysis revealed a 91% decrease in the odds of inflammatory disease among those with ≥1 pack-year of smoking after diagnosis among individuals with disease <8 yr. This was not influenced by disease location, family history of inflammatory bowel disease (IBD), or Jewish ethnicity.CONCLUSIONS:The prevalence of inflammatory CD decreased with time. Tobacco consumption was associated with this decline during the early phase of disease, suggesting that tobacco may influence the progression of inflammatory to stricturing or fistulizing type disease.

Colonoscopy in octogenarians: a prospective outpatient study

OBJECTIVES: The number of octogenarians (age ≥80 yr) referred for colonoscopy is increasing. Reported success rates regarding colonoscopy completion and adequacy of colonic preparation are poor overall in this group. This may be the result of age-related differences or biases due to retrospective data. The aims of this study were to prospectively determine differences between octogenarians and nonoctogenarians in adequacy of colonic preparation, success in completing colonoscopy, and complications of conscious sedation. METHODS: Prospective cohort study of 250 consecutive outpatients (150 nonoctogenarians and 100 octogenarians) referred for colonoscopy. Colonic preparation tolerance was assessed before colonoscopy, and the success rate and preparation were evaluated after the procedure. Conscious sedation complications were compared. RESULTS: In octogenarians and nonoctogenarians preparation tolerance (86% and 90%, respectively) was similar. Endoscopic success rate was slightly lower in octogenarians (90% vs 99%, p = 0.002). Preparation was poor in 16% of octogenarians compared with 4% of nonoctogenarians (p = 0.001). This was independent of the type of preparation used. Oxygen desaturation was more common in octogenarians (27% vs 19%, p = 0.0007) and associated with a higher meperidine dose (1.05 vs 0.75 mg/kg). No adverse outcomes occurred in either study group. CONCLUSIONS: Colonic preparations were well tolerated and colonoscopic success rates were high in octogenarians and nonoctogenarians. However, poor colonic preparation was four times as likely in octogenarians and was the most important impediment to adequate colonoscopy.

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. (Inflamm Bowel Dis 2007)

Is perianal Crohn's disease associated with intestinal fistulization?

BACKGROUND:When cases of Crohns disease (CD) are described as “fistulizing,” distinctions are often not drawn between perianal and intestinal fistulization. The question, therefore, remains open as to whether or not there is truly an association between perianal fistulization and intraabdominal intestinal fistulization in CD.AIMS:We have sought to determine the association between perianal and intestinal fistulization by analyzing the cases of CD recorded in databases from six international centers.PATIENTS:Six databases provided information on 5491 cases of CD in the United States, France, Italy, and The Netherlands. Of these cases, 1686 had isolated ileal disease and 1655 had Crohns colitis.METHODS:An association between perianal disease and internal fistulae was sought by calculating relative risks for the chance of internal fistulae among patients with perianal fistulae relative to those without. Statistical significance was calculated by the Mantel-Haenszel procedure, stratifying on the separate centers. All statistical tests and estimates were implemented using SAS for the PC.RESULTS:Among the 1686 cases with isolated ileal disease, the evidence of an association between perianal disease and internal fistulization was not consistent across centers, with relative risks ranging from 0.8 to 2.2. For patients with Crohns colitis (n = 1655), the association was much stronger and more consistent, with an estimated common relative risk of 3.4, 95% confidence interval (2.6–4.6, p < 0.0001).CONCLUSIONS:We have found a statistically significant association between perianal CD and intestinal fistulization, much stronger and more consistent in cases of Crohns colitis than in cases limited to the small bowel.

Immunomodulators Are Associated With a Lower Risk of First Surgery Among Patients With Non-Penetrating Non-Stricturing Crohn's Disease

OBJECTIVES:Early immunomodulator therapy may alter the natural history of Crohns disease in certain patients. We determined whether immunomodulator use was associated with a lower risk of first surgery among patients with non-stricturing non-penetrating Crohns disease.METHODS:A total of 159 consecutive patients with non-penetrating non-stricturing Crohns disease from 1994 to 2005 were retrospectively identified and followed from diagnosis to either first surgery (surgery group) or last clinic follow-up (medication group) in a historical cohort analysis. Immunomodulator use, duration, disease location, age at diagnosis, smoking, family history, and decade of diagnosis were compared. Cox proportional hazards models were adjusted for propensity score to determine whether immunomodulator use lasting >6 months decreased the risk of first surgery and whether duration of therapy affected risk.RESULTS:The median duration of follow-up was similar (6.0 vs. 5.5 years), age at diagnosis 10 years earlier, and isolated colonic disease three times less common (18 vs. 49%) in the surgery group as compared with the medication group. Immunomodulator use increased with time but overall was less common in the surgical group (24 vs. 48%). In the multivariate Cox proportional hazards model immunomodulator use was associated with a lower risk of surgery (hazard ratio, 0.41; 95% confidence interval 0.21–0.81) after adjustment for propensity score. Similarly, risk of surgery declined with duration of use.CONCLUSIONS:Immunomodulator use is associated with a decreased risk of first surgery among patients with non-stricturing non-penetrating CD. Early immunomodulator therapy may be beneficial in preventing first surgery in this population that has yet to develop penetrating or fistulizing complications.

Procedure time and the determination of polypoid abnormalities with experience: Implementation of a chromoendoscopy program for surveillance colonoscopy for ulcerative colitis

Background:Procedure length and agreement in detection of abnormalities may limit implementation of chromoendoscopy (CE) for dysplasia surveillance in ulcerative colitis (UC). We investigated these factors among endoscopists inexperienced in this technique. Methods:Six investigators performed surveillance colonoscopy with white light endoscopy (WLE) followed by CE on 75 patients with long-standing UC. Interobserver agreement for WLE and CE images of polyps and nonpolypoid mucosa was determined. Withdrawal times from the cecum were compared based on number of colonoscopies performed. Dysplasia detection rate with WLE was compared with CE. Results:The analysis of 586 images (266 WLE and 320 CE) from 57 patients included images of 160 polyps (64 flat) with 29 dysplastic lesions. All investigators identified 10/11 WLE images of dysplasia and 4 identified all 18 CE dysplasia images, 1 missed 1 and 1 missed 3. Four dysplastic lesions were not identified by 1 or more investigators and all measured <5 mm. Interobserver agreement for lesions was high with kappa scores of 0.91 and 0.86 for WLE and CE, respectively. Among the 75 patients enrolled, dysplasia was found in 9.3% with WLE compared with 21.3% with WLE and CE (P = 0.007). Median colonoscopy withdrawal time improved from 31 minutes for endoscopists performing fewer than 5 procedures to 18 minutes for 5 to 14 and 19 minutes for more than 15 procedures. Conclusions:Indigo carmine CE for UC surveillance resulted in high rates of interobserver agreement for polyp detection, acceptable withdrawal times, and enhanced dysplasia detection. These results are encouraging for the implementation of CE programs for chronic UC.

Rate of Early/Missed Colorectal Cancers After Colonoscopy in Older Patients With or Without Inflammatory Bowel Disease in the United States

OBJECTIVES:Patients with inflammatory bowel disease (IBD) have an increased risk for colorectal cancer (CRC). Previous studies on early/missed CRCs after colonoscopy excluded IBD patients. The aim of this study was to compare the rate of early/missed CRCs after colonoscopy among IBD and non-IBD patients, and identify factors associated with early/missed CRCs.METHODS:All patients in the Surveillance, Epidemiology and End-Results Medicare-linked database who were 67 years or older at colonoscopy during 1998–2005 and those who were subsequently diagnosed with CRC within 36 months were identified. CRCs diagnosed within 6 months of colonoscopy were categorized as detected CRCs; CRCs diagnosed 6–36 months after colonoscopy were categorized as early/missed CRCs. The rate of early/missed CRCs was calculated as number of early/missed CRCs divided by number of detected and early/missed CRCs. The χ2 test and multivariate logistic regression were used in statistical analysis.RESULTS:Of 55,008 CRC patients (304 Crohns disease; 544 ulcerative colitis (UC)), the rate of early/missed CRCs was 5.8% for non-IBD patients, 15.1% for Crohns, and 15.8% for UC (P<0.001). Compared with older non-IBD patients, early/missed CRCs among older IBD patients were less likely right-sided (both P<0.05). In multivariate logistic regression, the risk of early/missed CRCs was three times as high for IBD patients (Crohns odds ratio (OR), 3.07; 95% confidence interval (CI) 2.23–4.21; UC OR, 3.05; 95% CI, 2.44–3.81). Sensitivity analyses confirmed the robustness of this finding.CONCLUSIONS:Older IBD patients had a higher rate of early/missed CRCs after colonoscopy. Our finding supports intensive surveillance colonoscopy for older IBD patients as recommended by guidelines.