Histologic markers of inflammation in patients with ulcerative colitis in clinical remission.

BACKGROUND & AIMS: Mucosal healing, based on histologic analysis, is an end point of maintenance therapy for patients with ulcerative colitis (UC). There are few data on how histologic signs of inflammation correlate with endoscopic and peripheral blood measures of inflammation in these patients. We investigated patterns of histologic features of inflammation in patients with UC in clinical remission, and correlated these with endoscopic and biochemical measures of inflammation. METHODS: We performed a prospective observational study of 103 patients with UC in clinical remission undergoing surveillance colonoscopy while receiving maintenance therapy with mesalamine or thiopurines; 2674 biopsy specimens were collected from 708 colonic segments. Each colonic segment was evaluated based on the Mayo endoscopic subscore and the Geboes histology score (range, 0-5.4). Biomarkers were measured in peripheral blood samples. RESULTS: Histologic features of inflammation were found in 54% of patients receiving maintenance therapy; 37% had at least moderate inflammation based on histology scores. Of the 52 patients with endoscopic evidence only of left-sided colitis, 34% had histologic features of inflammation in their proximal colon. Histology scores correlated with endoscopic scores for per-segment inflammation (Spearman ρ = 0.65; P < .001). Patients with histology scores greater than 3.1 had a significantly higher mean level of C-reactive protein than those with scores less than 3.1. There were no differences among treatment groups in percentages of patients with histologic scores greater than 3.1. CONCLUSIONS: Patients in clinical remission from UC still frequently have histologic features of inflammation, which correlate with endoscopic appearance. Patients with at least moderate levels of inflammation, based on histologic grading (score >3.1), have higher serum levels of C-reactive protein, which could be used as a surrogate marker of histologic inflammation.

CD73 is a phenotypic marker of effector memory Th17 cells in inflammatory bowel disease.

Purinergic signaling and associated ectonucleotidases, such as CD39 and CD73, have been implicated in the pathogenesis of inflammatory bowel disease (IBD). CD39 is known to be a Treg memory cell marker, and here we determine the phenotype and function of CD73(+) CD4(+) T lymphocytes in patients with IBD. We describe elevated levels of CD73(+) CD4(+) T cells in the peripheral blood and intestinal lamina propria of patients with active IBD. The functional phenotype of these CD73(+) CD4(+) T cells was further determined by gene expression, ecto-enzymatic activity, and suppressive assays. Increased numbers of CD73(+) CD4(+) T cells in the periphery and lamina propria were noted during active inflammation, which returned to baseline levels following anti-TNF treatment. Peripheral CD73(+) CD4(+) T cells predominantly expressed CD45RO, and were enriched with IL-17A(+) cells. The CD73(+) CD4(+) cell population expressed higher levels of RORC, IL-17A, and TNF, and lower levels of FOXP3 and/or CD25, than CD73(-) CD4(+) T cells. Expression of CD73 by peripheral CD4(+) T cells was increased by TNF, and decreased by an anti-TNF monoclonal antibody (infliximab). In vitro, these peripheral CD73(+) CD4(+) T cells did not suppress proliferation of CD25(-) effector cells, and expressed higher levels of pro-inflammatory markers. We conclude that the CD73(+) CD4(+) T-cell population in patients with active IBD are enriched with cells with a T-helper type 17 phenotype, and could be used to monitor disease activity during treatment.

Predictors of endoscopic inflammation in patients with ulcerative colitis in clinical remission.

BACKGROUND: Patients with ulcerative colitis (UC) who are in clinical remission may still have underlying endoscopic inflammation, which is associated with inferior clinical outcomes. The goal of this study was to determine the prevalence of active endoscopic disease, and factors associated with it, in patients with UC who are in clinical remission. METHODS: Prospective observational study in a single center. Patients with UC in clinical remission (by Simple Clinical Colitis Activity Index) were enrolled prospectively at the time of surveillance colonoscopy. Disease phenotype, endoscopic activity (Mayo subscore), and histologic score (Geboes) were recorded, and blood was drawn for peripheral blood biomarkers. RESULTS: Overall, 149 patients in clinical remission were prospectively enrolled in this cohort; 81% had been in clinical remission for >6 months, and 86% were currently prescribed maintenance medications. At endoscopy, 45% of patients in clinical remission had any endoscopic inflammation (Mayo endoscopy subscore >0), and 13% had scores >1. In a multivariate model, variables independently associated with a Mayo endoscopic score >1 were remission for <6 months (P = 0.001), white blood count (P = 0.01), and C-reactive protein level (P = 0.009). A model combining these 3 variables had a sensitivity of 94% and a specificity of 73% for predicting moderate-to-severe endoscopic activity in patients in clinical remission (area under the curve, 0.86). In an unselected subgroup of patients who had peripheral blood mononuclear cell messenger RNA profiling, GATA3 messenger RNA levels were significantly higher in patients with endoscopic activity. CONCLUSIONS: Duration of clinical remission, white blood count, and C-reactive protein level can predict the probability of ongoing endoscopic activity, despite clinical remission in patients with UC. These parameters could be used to identify patients who require intensification of treatment to achieve mucosal healing.

Role of PET and combination PET/CT in the evaluation of patients with inflammatory bowel disease.

BACKGROUND: Positron emission tomography (PET) is a nuclear imaging technique providing noninvasive, three-dimensional, whole-body, quantitative images. The primary use of PET is in tumor detection and staging. More recently, it has been shown to be of value in assessing patients with inflammatory processes. To date the role of PET in the management of patients with inflammatory bowel disease (IBD) has not been defined. METHODS: The electronic literature (August 1966 to June 2008) on the utilization of PET in IBD was reviewed. Further references were obtained by cross-referencing from key articles. RESULTS: There have been no randomized studies to date examining the role of PET in the management of patients with IBD. Comparative studies have demonstrated a high degree of correlation between PET-detected segmental (18)F-fluorodeoxyglucose uptake and sites of macroscopic and histological inflammation noted on endoscopy. Prospectively, PET performs favorably in comparison to conventional imaging modalities for IBD such as immunoscintigraphy, magnetic resonance imaging (MRI), and hydro-MRI. Several case series have highlighted the utility of PET in the diagnosis of IBD in the pediatric population. The recent development of PET/computed tomography (CT) combines the physiological sensitivity of PET with the anatomical accuracy of CT, increasing the specificity of PET. CONCLUSIONS: The case series and nonrandomized studies published to date emphasize the utility of PET in assessing patients with IBD and justify further study. The development of PET/CT represents a significant advance and should be considered in the evaluation of patients with IBD.

Incident rates of colonic neoplasia in older patients: when should we stop screening?

INTRODUCTION: Current guidelines endorse colon cancer screening every 5-10 years in patients over 50 years of age. However, there is no consensus regarding what age is appropriate to stop screening. The aim of this study was to characterize neoplasia occurrence/recurrence in a large cohort of patients > or =70 years of age undergoing colonoscopy. METHODS: The Mayo Rochester endoscopic database was reviewed to determine the incidence of colonic neoplasia in patients > or =70 years undergoing two colonoscopies at least 12 months apart between January 1996 and December 2000. Patients were classified based on (i) age: 70-74, 75-79, > or =80 years; and (ii) polyp detection on initial examination, that is, subsequent examination for screening or surveillance. RESULTS: Overall, 1353 patients underwent two colonoscopies at least 12 months apart (median interval 140 weeks) with removal of polyp on initial examination in 726 (53.7%) patients (surveillance cohort). On subsequent endoscopy, polyps > or =10 mm were detected in 54 (4.0%) and cancer in 13 (1.0%) patients. All age groups were well matched with respect to detection of neoplasia on index examination (P = 0.9) and polyp size on initial colonoscopy among the surveillance group (P = 0.9). Using a Cox proportional hazards model, adjusted hazard ratios (95% confidence interval [CI]) for neoplasia (polyps > or =10 mm) were: 2.0 (1.50-2.73, P < 0.0001) (surveillance vs screening), 1.33 (0.96-1.79, P = 0.08) (> or =80 vs 70-74), and 1.05 (0.78-1.38, P = 0.75) (75-79 vs 70-74). Adjusted hazard ratios for development of cancer were: 1.87 (1.03-3.97, P = 0.04) (surveillance vs screening), 1.73 (0.84-3.56, P = 0.13) (> or =80 vs 70-74), and 1.38 (0.71-2.77, P = 0.34) (75-79 vs 70-74). CONCLUSIONS: Prior history of neoplasia remains a strong risk factor for colorectal neoplasia development in elderly patients and should be considered when deciding the need for continuing screening/surveillance. Incident neoplasia rates in a previously screened elderly population rise slowly with advancing age although cancer rates rise more sharply. Therefore, screening still retains a role in elderly patients; however, clinical judgment is still required to individualize screening practice. As the risk of competing comorbid illnesses continues to increase over time, the threshold to perform colon screening should increase accordingly.

Incident rates of colonic neoplasia according to age and gender: implications for surveillance colonoscopy intervals.

INTRODUCTION: Current guidelines endorse surveillance colonoscopy at 3 to 5 years following initial detection of neoplasia. However, individual patients' risks may vary according to age and gender. This study aimed to characterize neoplasia recurrence in a large patient cohort undergoing surveillance colonoscopy. METHODS: All patients undergoing two colonoscopies at least 12 months apart between 1996 and 2000, with detection and removal of a polyp on the index colonoscopy, were identified using our endoscopic database to determine the incidence of colonic neoplasia. Patients were classified according to age (<50, 50-64, 65-74, > or =75 years) and gender. RESULTS: Overall, 1803 patients underwent two colonoscopies at least 12 months apart (median interval, 140 weeks) with removal of a polyp on initial examination. Polyps > or =5 mm were detected in 334 (19%) patients and polyps > or =10 mm in 105 (6%) on subsequent endoscopy. All age and gender groups were well matched with respect to size of polyp detected on initial colonoscopy (P = 0.2). Kaplan-Meier curves and a Cox proportional hazards model demonstrated similar rates of neoplasia recurrence for all patients irrespective of age and gender. CONCLUSIONS: Similar rates of neoplasia recurrence were observed among patients of different gender and age groups on surveillance colonoscopy. From a health resource utilization perspective, these findings support current recommendations for similar surveillance intervals for patients regardless of age and gender.