Erik Mooiweer

Low fecal calprotectin predicts sustained clinical remission in inflammatory bowel disease patients : a plea for deep remission

BACKGROUND AND AIMS Mucosal healing has become the treatment goal in patients with ulcerative colitis (UC) and Crohns disease (CD). Whether low fecal calprotectin levels and histological healing combined with mucosal healing is associated with a further reduced risk of relapses is unknown. METHODS Patients with CD, UC or inflammatory bowel disease-unclassified (IBD-U) scheduled for surveillance colonoscopy collected a stool sample prior to bowel cleansing. Only patients with mucosal healing (MAYO endoscopic score of 0) were included. Fecal calprotectin was measured using a quantitative enzyme-linked immunosorbent assay (R-Biopharm, Germany). Biopsies were obtained from four colonic segments, and histological disease severity was assessed using the Geboes scoring system. Patients were followed until the last outpatient clinic visit or the development of a relapse, which was defined as IBD-related hospitalization, surgery or step-up in IBD medication. RESULTS Of the 164 patients undergoing surveillance colonoscopy, 92 patients were excluded due to active inflammation or missing biopsies. Of the remaining 72 patients (20 CD, 52 UC or IBD-U), six patients (8%) relapsed after a median follow-up of 11 months (range 5-15 months). Median fecal calprotectin levels at baseline were significantly higher for patients who relapsed compared with patients who maintained remission (284 mg/kg vs. 37 mg/kg. p < 0.01). Fecal calprotectin below 56 mg/kg was found to optimally predict absence of relapse during follow-up with 64% sensitivity, 100% specificity, 100% negative predictive value and 20% positive predictive value. The presence or absence of active inflammation determined by Geboes cut-off score of 3.1 was less strongly associated with the risk of relapse (64% sensitivity, 33% specificity, 9% negative predictive value and 92% positive predictive value. CONCLUSION Low calprotectin levels identify IBD patients who remain in stable remission during follow-up.

Incidence of Interval Colorectal Cancer Among Inflammatory Bowel Disease Patients Undergoing Regular Colonoscopic Surveillance

BACKGROUND & AIMS Surveillance is recommended for patients with long-term inflammatory bowel disease because they have an increased risk of colorectal cancer (CRC). To study the effectiveness of surveillance, we determined the incidence of CRC after negative findings from surveillance colonoscopies (interval CRC). METHODS We collected data from 1273 patients with ulcerative colitis or Crohns disease, enrolled in a surveillance program at 7 hospitals in The Netherlands, who underwent 4327 surveillance colonoscopies from January 1, 2000, through January 1, 2014. Patients were followed up from their first surveillance colonoscopy until the last surveillance colonoscopy, colectomy, or CRC. Factors that might have contributed to the occurrence of CRC were categorized as inadequate procedures (ie, inadequate bowel preparation), inadequate surveillance (CRC occurring outside the appropriate surveillance interval), or inadequate management of dysplasia (CRC diagnosed in the same colonic segment as a previous diagnosis of dysplasia). The remaining CRC cases were classified as true interval CRCs. RESULTS CRC was diagnosed in 17 patients (1.3%), with an incidence of 2.5 per 1000 years of follow-up evaluation. Factors that might account for the occurrence of CRC were identified in 12 patients (70%). These were inadequate colonoscopies in 4 patients (24%), inadequate surveillance intervals in 9 patients (53%), and inadequate management of dysplasia in 2 patients (12%). The remaining 5 cases of CRC (30%) were classified as true interval CRCs. CONCLUSIONS In a retrospective analysis of patients with inflammatory bowel disease participating in a surveillance program, the incidence of CRC was only 1%, which supports the implementation of longer surveillance intervals. However, the fact that 30% of CRC cases were interval cancers indicates the need for variable surveillance intervals based on risk factors for CRC.

Fecal Hemoglobin and Calprotectin Are Equally Effective in Identifying Patients with Inflammatory Bowel Disease with Active Endoscopic Inflammation

Background:Fecal calprotectin can be used as a noninvasive tool to assess inflammation in patients with inflammatory bowel disease (IBD). However, the diagnostic accuracy of calprotectin is modest, and therefore additional markers are needed. We compared the efficacy of fecal hemoglobin and calprotectin as markers for endoscopic inflammation in patients with IBD. Methods:Consecutive patients with Crohns disease or ulcerative colitis scheduled for surveillance colonoscopy collected a stool sample before bowel preparation. Experienced endoscopists assessed the presence of inflammation in each colonic segment. Fecal calprotectin and hemoglobin were analyzed with an enzyme-linked immunosorbent assay. Receiver operator characteristic statistics were used to determine cutoff values for calprotectin and hemoglobin. Results:A total of 176 surveillance colonoscopies were performed in 164 patients, of which 83 patients had Crohns disease, 74 had ulcerative colitis, and 7 IBD-unclassified. Median (interquartile range) calprotectin and hemoglobin concentrations were 137 mg/kg (interquartile range, 33–494) and 0.51 &mgr;g/g (interquartile range, 0.18–8.50), respectively. For calprotectin, a cutoff value of 140 mg/kg predicted endoscopic inflammation with 86% sensitivity, 72% specificity, 64% positive predictive value, 90% negative predictive value, and an area under the curve of 0.87. For hemoglobin, a cutoff value of 1.51 &mgr;g/g indicated endoscopic inflammation with 74% sensitivity, 84% specificity, 72% positive predictive value, 84% negative predictive value, and an area under the curve of 0.81. Combining both tests did not increase the predictive accuracy substantially compared with calprotectin or hemoglobin alone (area under the curve, 0.88). Conclusions:Fecal hemoglobin can identify patients with IBD with active inflammation with a predictive accuracy similar to calprotectin.

Adenomas in patients with inflammatory bowel disease are associated with an increased risk of advanced neoplasia.

Background:It is still unclear whether inflammatory bowel disease (IBD) patients with adenomas have a higher risk of developing high-grade dysplasia (HGD) or colorectal cancer (CRC) than non-IBD patients with sporadic adenomas. We compared the risk of advanced neoplasia (AN, defined as HGD or CRC) in IBD patients with adenomas to IBD patients without adenomas and patients without IBD with adenomas. Methods:IBD patients with a histological adenoma diagnosis (IBD + adenoma), age-matched IBD patients without adenoma (IBD-nonadenoma), and adenoma patients without IBD (nonIBD + adenoma) were enrolled in this study. Medical charts were reviewed for adenoma characteristics and development of AN. The endoscopic appearance of the adenomas was characterized as typical (solitary sessile or pedunculated) or atypical (all other descriptions). Results:A total of 110 IBD + adenoma patients, 123 IBD-nonadenoma patients, and 179 nonIBD + adenoma patients were included. Mean duration of follow-up was 88 months (SD ±41). The 5-year cumulative risks of AN were 11%, 3%, and 5% in IBD + adenoma, IBD-nonadenoma, and nonIBD + adenoma patients, respectively (P < 0.01). In IBD patients atypical adenomas were associated with a higher 5-year cumulative risk of AN compared to IBD patients with typical adenomas (18% vs. 7%, P = 0.03). Conclusions:IBD patients with a histological diagnosis of adenoma have a higher risk of developing AN than adenoma patients without IBD and IBD patients without adenomas. The presence of atypical adenomas in particular was associated with this increased risk, although patients with typical adenomas were found to carry an additional risk as well.

Neoplasia yield and colonoscopic workload of surveillance regimes for colorectal cancer in colitis patients: a retrospective study comparing the performance of the updated AGA and BSG guidelines.

Background:Due to the increased risk of colorectal cancer, colonoscopic surveillance is recommended for patients with ulcerative and Crohns colitis. Because surveillance intervals differ considerably between the recently updated American Gastroenterological Association (AGA) and British Society of Gastroenterology (BSG) guidelines, we compared the neoplasia yield and colonoscopic workload of these guidelines. Methods:Patients with inflammatory bowel disease undergoing surveillance were identified using medical records. Patients were stratified according to the BSG and AGA guidelines, and corresponding colonoscopic workload was calculated based on the risk factors present during follow-up. The incidence of colitis-associated neoplasia (CAN), defined as a low-grade dysplasia in flat mucosa or a non–adenoma-like mass, high-grade dysplasia, or colorectal cancer was compared between the risk groups of either guidelines. Results:In total, 1018 patients with inflammatory bowel disease who underwent surveillance were identified. Using the AGA surveillance intervals, 64 patients (6%) were assigned to annual and 954 patients (94%) to biannual surveillance, resulting in 541 colonoscopies per year. The yield of CAN was 5.3% and 20.3% in the low- and high-risk groups, respectively (P = 0.02). Using the BSG surveillance intervals, 204 patients received surveillance annually (20%), 393 patients every 3 years (39%), and 421 patients every 5 years (41%), resulting in 420 colonoscopies per year, which is 22% lower than the AGA guidelines. The yield of CAN was 3.6%, 6.9%, and 10.8%, for the low-, intermediate-, and high-risk groups, respectively (P = 0.26). Conclusions:Although the BSG surveillance intervals offer the advantage of a lower colonoscopic workload, the risk stratification of the AGA seems superior in distinguishing patients at higher risk of CAN.

Low Rate of Dysplasia Detection in Mucosa Surrounding Dysplastic Lesions in Patients Undergoing Surveillance for Inflammatory Bowel Diseases

BACKGROUND & AIMS: When dysplastic lesions are encountered during surveillance colonoscopy of patients with inflammatory bowel disease (IBD), guidelines recommend collection of additional biopsies from the surrounding mucosa to ensure the lesion has been adequately circumscribed. We aimed to determine the rate of dysplasia in mucosa biopsies collected from tissues surrounding dysplastic lesions during IBD surveillance. METHODS: In a retrospective study, we collected endoscopy and pathology reports from 1065 patients undergoing colonoscopic surveillance for IBD from 2000 through 2015 at 3 centers in the Netherlands. We analyzed reports from all patients with dysplastic lesions from whom biopsies of surrounding mucosa were collected. Among 194 patients with 1 or more visible dysplastic lesions, mucosal biopsies were collected from tissues adjacent to 140 dysplastic lesions from 71 patients (63% male; 48% with ulcerative colitis, 42% with Crohns disease, and 10% with indeterminate colitis). RESULTS: The mean number of surrounding mucosa biopsies collected per lesion was 3.4 (range, 1–6). Dysplasia was detected in 7 biopsies surrounding 140 areas of dysplasia (5.0%) and 5 biopsies surrounding 136 areas of low‐grade dysplasia (3.7%). Dysplasia in biopsies of surrounding mucosa could be observed during 5 of 87 white light endoscopies and during 2 of 53 chromoendoscopies. In patients with dysplasia in mucosa surrounding lesions of low‐grade dysplasia, post‐resection surveillance did not reveal high‐grade dysplasia or colorectal cancer. CONCLUSIONS: Dysplasia is detected in only 5% of biopsies collected from mucosa surrounding dysplastic lesions. This observation indicates that endoscopists accurately delineate the borders of dysplastic lesions during surveillance of patients with IBD. The lack of clinical consequences from routinely collecting biopsies from areas surrounding dysplastic lesions casts doubt on the usefulness and cost‐effectiveness of this practice.

A risk-profiling approach for surveillance of inflammatory bowel disease-colorectal carcinoma is more cost-effective: a comparative cost-effectiveness analysis between international guidelines

BACKGROUND Colonoscopic surveillance for neoplasia is recommended for patients with inflammatory bowel disease (IBD)-related colitis. However, data on cost-effectiveness predate current international guidelines. OBJECTIVE To compare cost-effectiveness based on contemporary data between the surveillance strategies of the American Gastroenterological Association (AGA) and British Society of Gastroenterology (BSG). DESIGN We constructed a Markov decision model to simulate the clinical course of IBD patients. SETTING We compared the 2 surveillance strategies for a base case of a 40-year-old colitis patient who was followed for 40 years. PATIENTS AGA surveillance distinguishes 2 groups: a high-risk group with annual surveillance and an average-risk group with biannual surveillance. BSG surveillance distinguishes 3 risk groups with yearly, 3-year, or 5-year surveillance. INTERVENTIONS Patients could move from a no-dysplasia state with colonoscopic surveillance to 1 of 3 states for which proctocolectomy was indicated: (1) dysplasia/local cancer, (2) regional/metastasized cancer, or (3) refractory disease. After proctocolectomy, a patient moved to a no-colon state without surveillance. MAIN OUTCOME MEASUREMENTS Direct costs of medical care, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. RESULTS BSG surveillance dominated AGA surveillance with

Clinical implications of low grade dysplasia found during inflammatory bowel disease surveillance: a retrospective study comparing chromoendoscopy and white-light endoscopy

9846 per QALY. Both strategies were equally effective with 24.16 QALYs, but BSG surveillance was associated with lower costs because of fewer colonoscopies performed. Costs related to IBD, surgery, or cancer did not affect cost-effectiveness. LIMITATIONS The model depends on the accuracy of derived data, and the assumptions that were made to reflect real-life situations. Study conclusions may only apply to the U.S. health care system. CONCLUSION The updated risk-profiling approach for surveillance of IBD colorectal carcinoma by the BSG guideline appears to be more cost-effective.

Low interobserver agreement among endoscopists in differentiating dysplastic from non-dysplastic lesions during inflammatory bowel disease colitis surveillance

Background and study aims Current guidelines recommend the use of pancolonic chromoendoscopy for surveillance of patients with inflammatory bowel disease (IBD). It is currently unknown whether low grade dysplasia (LGD) found using chromoendoscopy carries a similar risk of high grade dysplasia (HGD) or colorectal cancer (CRC) compared with LGD detected using white-light endoscopy (WLE). The aim of this study was to compare the risk of advanced neoplasia, a combined endpoint of HGD and CRC, during follow-up after detection of lesions containing LGD identified with either chromoendoscopy or WLE. Patients and methods A retrospective cohort was established to identify patients who underwent IBD surveillance for ulcerative colitis or colonic Crohns disease between 2000 and 2014. Subgroups were identified, based on the endoscopic technique (standard definition resolution WLE, high definition resolution WLE or chromoendoscopy). LGD detected in random biopsies was considered invisible LGD. Patients were followed until detection of advanced neoplasia, colectomy, death, or the last known surveillance colonoscopy. Results Of 1065 patients undergoing IBD surveillance, 159 patients underwent follow-up for LGD, which was visible in 133 cases and invisible in 26 cases. On follow-up, five cases of HGD and five cases of CRC were detected. The overall incidence rate of advanced neoplasia was 1.34 per 100 patient-years with a median follow-up of 4.7 years and a median time to advanced neoplasia of 3.3 years. There were no significant differences in the incidence of advanced neoplasia between chromoendoscopy-detected and WLE-detected LGD. Conclusion Advanced neoplasia was found to develop infrequently after detection of LGD in patients undergoing endoscopic surveillance for IBD. LGD lesions detected with either chromoendoscopy or WLE carry similar risks of advanced neoplasia over time.

Disease severity does not affect the interval between IBD diagnosis and the development of CRC: Results from two large, Dutch case series

Abstract Objectives. During endoscopic surveillance in patients with longstanding colitis, a variety of lesions can be encountered. Differentiation between dysplastic and non-dysplastic lesions can be challenging. The accuracy of visual endoscopic differentiation and interobserver agreement (IOA) has never been objectified. Material and methods. We assessed the accuracy of expert and nonexpert endoscopists in differentiating (low-grade) dysplastic from non-dysplastic lesions and the IOA among and between them. An online questionnaire was constructed containing 30 cases including a short medical history and an endoscopic image of a lesion found during surveillance employing chromoendoscopy. Results. A total of 17 endoscopists, 8 experts, and 9 nonexperts assessed all 30 cases. The overall sensitivity and specificity for correctly identifying dysplasia were 73.8% (95% confidence interval (CI) 62.1–85.4) and 53.8% (95% CI 42.6–64.7), respectively. Experts showed a sensitivity of 76.0% (95% CI 63.3–88.6) versus 71.8% (95% CI 58.5–85.1, p = 0.434) for nonexperts, the specificity 61.0% (95% CI 49.3–72.7) versus 47.1% (95% CI 34.6–59.5, p = 0.008). The overall IOA in differentiating between dysplastic and non-dysplastic lesions was fair 0.24 (95% CI 0.21–0.27); for experts 0.28 (95% CI 0.21–0.35) and for nonexperts 0.22 (95% CI 0.17–0.28). The overall IOA for differentiating between subtypes was fair 0.21 (95% CI 0.20–0.22); for experts 0.19 (95% CI 0.16–0.22) and nonexpert 0.23 (95% CI 0.20–0.26). Conclusion. In this image-based study, both expert and nonexpert endoscopists cannot reliably differentiate between dysplastic and non-dysplastic lesions. This emphasizes that all lesions encountered during colitis surveillance with a slight suspicion of containing dysplasia should be removed and sent for pathological assessment.