David T. Rubin

Analysis of air contrast barium enema, computed tomographic colonography, and colonoscopy: prospective comparison.

BACKGROUND The usefulness of currently available colon imaging tests, including air contrast barium enema (ACBE), computed tomographic colonography (CTC), and colonoscopy, to detect colon polyps and cancers is uncertain. We aimed to assess the sensitivity of these three imaging tests. METHODS Patients with faecal occult blood, haematochezia, iron-deficiency anaemia, or a family history of colon cancer underwent three separate colon-imaging studies--ACBE, followed 7-14 days later by CTC and colonoscopy on the same day. The primary outcome was detection of colonic polyps and cancers. Outcomes were assessed by building an aggregate view of the colon, taking into account results of all three tests. FINDINGS 614 patients completed all three imaging tests. When analysed on a per-patient basis, for lesions 10 mm or larger in size (n=63), the sensitivity of ACBE was 48% (95% CI 35-61), CTC 59% (46-71, p=0.1083 for CTC vs ACBE), and colonoscopy 98% (91-100, p<0.0001 for colonoscopy vs CTC). For lesions 6-9 mm in size (n=116), sensitivity was 35% for ACBE (27-45), 51% for CTC (41-60, p=0.0080 for CTC vs ACBE), and 99% for colonoscopy (95-100, p<0.0001 for colonoscopy vs CTC). For lesions of 10 mm or larger in size, the specificity was greater for colonoscopy (0.996) than for either ACBE (0.90) or CTC (0.96) and declined for ACBE and CTC when smaller lesions were considered. INTERPRETATION Colonoscopy was more sensitive than other tests, as currently undertaken, for detection of colonic polyps and cancers. These data have important implications for diagnostic use of colon imaging tests.

Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target.

OBJECTIVES:The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program was initiated by the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD). It examined potential treatment targets for inflammatory bowel disease (IBD) to be used for a “treat-to-target” clinical management strategy using an evidence-based expert consensus process.METHODS:A Steering Committee of 28 IBD specialists developed recommendations based on a systematic literature review and expert opinion. Consensus was gained if ≥75% of participants scored the recommendation as 7–10 on a 10-point rating scale (where 10=agree completely).RESULTS:The group agreed upon 12 recommendations for ulcerative colitis (UC) and Crohn’s disease (CD). The agreed target for UC was clinical/patient-reported outcome (PRO) remission (defined as resolution of rectal bleeding and diarrhea/altered bowel habit) and endoscopic remission (defined as a Mayo endoscopic subscore of 0–1). Histological remission was considered as an adjunctive goal. Clinical/PRO remission was also agreed upon as a target for CD and defined as resolution of abdominal pain and diarrhea/altered bowel habit; and endoscopic remission, defined as resolution of ulceration at ileocolonoscopy, or resolution of findings of inflammation on cross-sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy. Biomarker remission (normal C-reactive protein (CRP) and calprotectin) was considered as an adjunctive target.CONCLUSIONS:Evidence- and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD are made available. Prospective studies are needed to determine how these targets will change disease course and patients’ quality of life.

Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease.

BACKGROUND & AIMS Some women with inflammatory bowel disease require therapy with tumor necrosis factor (TNF) antagonists during pregnancy. It is not clear whether these drugs are transferred to the fetus via the placenta and then cleared, or whether structurally different TNF antagonists have different rates of transfer. METHODS We studied 31 pregnant women with inflammatory bowel disease receiving infliximab (IFX, n = 11), adalimumab (ADA, n = 10), or certolizumab (CZP, n = 10). Serum concentrations of the drugs were measured at birth in the mother, infant, and in cord blood, and then monthly in the infant until the drugs were undetectable. Drug concentrations in the cord and the infant at birth were compared with those of the mother. RESULTS Concentrations of IFX and ADA, but not CZP, were higher in infants at birth and their cords than in their mothers. The levels of CZP in infants and their cords were less than 2 μg/mL. The median level of IFX in the cord was 160% that of the mother, the median level of ADA in the cord was 153% that of the mother, and the median level of CZP in the cord was 3.9% that of the mother. IFX and ADA could be detected in the infants for as long as 6 months. No congenital anomalies or serious complications were reported. CONCLUSIONS The TNF antagonists IFX and ADA are transferred across the placenta and can be detected in infants at birth; the drugs were detected in infants up to 6 months after birth. CZP has the lowest level of placental transfer, based on levels measured in cords and infants at birth, of the drugs tested.

Fecal microbiota transplantation as therapy for inflammatory bowel disease: A systematic review and meta-analysis

BACKGROUND AND AIMS Fecal microbiota transplantation (FMT) has gained interest as a novel treatment option for inflammatory bowel diseases (IBD). While publications describing FMT as therapy for IBD have more than doubled since 2012, research that investigates FMT treatment efficacy has been scarce. We conducted a systematic review and meta-analysis to evaluate the efficacy of FMT as treatment for patients with IBD. METHODS A systematic literature search was performed through May 2014. Inclusion criteria required FMT as the primary therapeutic agent. Clinical remission (CR) and/or mucosal healing were defined as primary outcomes. Studies were excluded if they did not report clinical outcomes or included patients with infections. RESULTS Eighteen studies (9 cohort studies, 8 case studies and 1 randomized controlled trial) were included. 122 patients were described (79 ulcerative colitis (UC); 39 Crohns disease (CD); 4 IBD unclassified). Overall, 45% (54/119) of patients achieved CR during follow-up. Among the cohort studies, the pooled proportion of patients that achieved CR was 36.2% (95% CI 17.4%-60.4%), with a moderate risk of heterogeneity (Cochrans Q, P=0.011; I(2)=37%). Subgroup analyses demonstrated a pooled estimate of clinical remission of 22% (95% CI 10.4%-40.8%) for UC (P=0.37; I(2)=0%) and 60.5% (95% CI 28.4%-85.6%) for CD (P=0.05; I(2)=37%). Six studies performed microbiota analysis. CONCLUSIONS This analysis suggests that FMT is a safe, but variably efficacious treatment for IBD. More randomized controlled trials are needed and should investigate frequency of FMT administration, donor selection and standardization of microbiome analysis.

Evaluation of Diffusion-weighted MR Imaging for Detection of Bowel Inflammation in Patients with Crohn's Disease

RATIONALE AND OBJECTIVES The aims of this study were to determine the feasibility of diffusion-weighted magnetic resonance imaging (DWI) in the detection of bowel inflammation and to investigate the changes in apparent diffusion coefficient (ADC) values in the inflamed bowel in patients with Crohns disease. MATERIALS AND METHODS Eleven patients who underwent magnetic resonance enterography (including DWI) for Crohns disease and colonoscopy or surgery within 4 weeks of examination were recruited. Two radiologists reviewed diffusion-weighted images and ADC maps to evaluate for inflammation in each bowel segment (terminal ileum, cecum, ascending colon, transverse colon, descending colon, and rectosigmoid colon) and measured the ADC values of each bowel segment. Endoscopic and pathologic results were correlated with DWI findings. RESULTS Fifty-three segments (19 with inflammation, 34 normal) were included. DWI detected inflammation in 18 of 19 segments (94.7%) and showed normal results in 28 of 34 segments (82.4%). On diffusion-weighted images, bowel segments with inflammation revealed higher signal compared to normal segments. Artifact levels were none or minimal in 10 of 11 patients (90.9%) and moderate in one patient. On quantitative analysis, ADC values of inflamed and normal bowel were measured as 0.47 - 2.60 x 10(-3) and 1.39 - 4.03 x 10(-3) mm(2)/s, respectively (P < .05). CONCLUSION DWI with parallel imaging is a feasible technique for the detection of inflammation in patients with Crohns disease. ADC values are decreased in inflamed bowel segments, indicating restricted diffusion.

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?

Active Crohn's disease in the small bowel: evaluation by diffusion weighted imaging and quantitative dynamic contrast enhanced MR imaging.

To determine relative diagnostic value of MR diffusion and perfusion parameters in detection of active small bowel inflammation in patients with Crohns disease (CD).

Agile patency system eliminates risk of capsule retention in patients with known intestinal strictures who undergo capsule endoscopy.

BACKGROUND Capsule endoscopy (CE) of the small bowel has become a standard diagnostic tool, but there have been concerns regarding the risk of capsule retention in certain high-risk groups. The Agile patency system, an ingestible and dissolvable capsule with an external scanner, was developed to allow physicians to perform CE with greater confidence that the capsule will be safely excreted in patients at risk for capsule retention. OBJECTIVE Our purpose was to assess the ability of the device to help physicians identify which patients with known strictures may safely undergo CE. DESIGN Patients with known strictures ingested the new patency capsule and underwent periodic scanning until it was excreted. The intestinal tract was considered to be sufficiently patent if the capsule was excreted intact or if the capsule was not detected by the scanner at 30 hours after ingestion. If patency was established, then standard CE was performed. SETTING International multicenter study. PATIENTS A total of 106 patients with known strictures. INTERVENTION Agile patency system. MAIN OUTCOME MEASUREMENTS Performance and safety of Agile patency system. RESULTS A total of 106 patients ingested the patency capsule. Fifty-nine (56%) excreted it intact and subsequently underwent CE. There were no cases of capsule retention. Significant findings on CE were found in 24 (41%). There were 3 severe adverse events. CONCLUSIONS These results suggest that the Agile patency system is a useful tool for physicians to use before CE in patients with strictures to avoid retention. This group of patients may have a high yield of clinically significant findings at CE. This capsule may determine whether patients who have a contraindication to CE may safely undergo CE and obtain useful diagnostic information.

Claudin-1 and claudin-2 expression is elevated in inflammatory bowel disease and may contribute to early neoplastic transformation

Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal adenocarcinoma. The factors that result in IBD-associated carcinogenesis are not understood. We hypothesized that altered expression of intestinal epithelial tight junction proteins might contribute to neoplastic progression. Semiquantitative immunohistochemical staining of human biopsies was used to assess expression of the tight junction proteins claudin-1, claudin-2, claudin-4, and occludin in IBD, IBD-associated dysplasia, acute, self-limited colitis (ASLC), and sporadic adenomas. Claudin-1 and claudin-2 expression was elevated in active IBD, adenomas, and IBD-associated dysplasia, but not ASLC. In contrast, claudin-4 expression was elevated in both active IBD and ASLC. Occludin expression was similar to control in all cases. Importantly, in IBD, claudin-1 and claudin-2 expression correlated positively with inflammatory activity. To investigate mechanisms underlying altered claudin expression, β-catenin activation was assessed as nuclear localization. Like claudin-1 and claudin-2, β-catenin was markedly activated in IBD, sporadic dysplasia, and IBD-associated dysplasia, but was only slightly activated in ASLC. Taken together, these data suggest that β-catenin transcriptional activity is elevated in chronic injury and that this may contribute to increased claudin-1 and claudin-2 expression. We speculate that increased claudin-1 and claudin-2 expression may be involved at early stages of transformation in IBD-associated neoplasia.

5-aminosalicylic acid therapy and the risk of colorectal cancer among patients with inflammatory bowel disease

Background: Patients with inflammatory bowel disease (IBD) affecting the colon are at increased risk of developing colorectal cancer (CRC). Published data are conflicting about whether 5‐aminosalicylic acid (5‐ASA) has chemopreventive properties against IBD‐related carcinogenesis. The objective of this observational study was to determine if an association between 5‐ASA therapy and CRC risk exists in IBD patients. Methods: Adult patients with a new CRC diagnosis (n = 18,440) were identified from 2 large administrative claims databases. For each case, 20 control patients with no record of CRC diagnosis or bowel surgery (n = 368,800) were identified. Results: An IBD diagnosis was associated with a 6‐ to 7‐fold increased risk of CRC (ulcerative colitis, crude odds ratio [OR] = 6.72, 95% CI, 5.79–7.81; Crohns disease, crude OR = 6.60, 95% CI, 5.56–7.82). Among patients with IBD (364 CRC cases, 1172 controls), exposure to 5‐ASA therapy of any dose or duration during the 12 months before CRC diagnosis was not associated with a reduced risk of CRC (OR = 0.97; 95% CI, 0.77–1.23). However, there was a trend toward a decreased risk of CRC with increasing number of mesalamine prescriptions in the previous year, though statistical significance was not achieved (trend P = 0.08). Conclusions: Treating IBD patients with 5‐ASA medications was not found to have a protective effect against colitis‐related CRC when assessed over a short period of exposure.