E Calabrese

Wireless capsule endoscopy and small intestine contrast ultrasonography in recurrence of Crohn's disease

Background: The best available tool to assess recurrence of Crohns disease (CD) is ileocolonoscopy (CC). Small intestine contrast ultrasonography (SICUS) and wireless capsule endoscopy (WCE) are noninvasive techniques able to detect small bowel lesions. In a prospective longitudinal study, we aimed to investigate the usefulness of SICUS and WCE for assessing postoperative recurrence of CD 1 year after surgery, using CC as the gold standard. Methods: Twenty‐two patients (11 men, median age 33 years, range 22–67 years) undergoing ileocolonic resection for CD were prospectively followed from July 2003 to May 2006, with the Crohns Disease Activity Index (CDAI) used for clinical assessment every 3 months for 1 year. At 1 year, recurrence was assessed by SICUS and CC, followed by WCE. CD recurrence was assessed by CC (Rutgeerts score). SICUS was performed after ingestion of polyethylene glycol, and WCE was performed with Given M2A equipment. Results: At 1 year, all 22 patients had inactive CD (CDAI < 150). In 5 patients, WCE was not performed because of luminal narrowing or stenosis. Seventeen of the 22 patients had all 3 techniques performed. CC detected recurrence in 21 of 22 patients. Lesions compatible with recurrence were detected by SICUS in all 22 patients (1 false positive). When considering only the 17 patients studied by all 3 techniques, recurrence was detected by CC in 16 of 17 patients, whereas lesions compatible with recurrence were detected by SICUS in all 17 patients (16 true positives [TPs], 1 FP) and by WCE in 16 of 17 patients (16 TPs, 1 true negative). Conclusions: The present findings suggest that SICUS and WCE may be used as noninvasive techniques for the assessment of recurrence of CD in patients being regularly followed up after ileocolonic resection. (Inflamm Bowel Dis 2007)

Phase I Clinical Trial of Smad7 Knockdown Using Antisense Oligonucleotide in Patients With Active Crohn's Disease

In the gut of patients with Crohns disease (CD), high Smad7 blocks the immune-suppressive activity of transforming growth factor (TGF)-β1, thereby contributing to amplify inflammatory signals. In vivo in mice, knockdown of Smad7 with a Smad7 antisense oligonucleotide (GED0301) attenuates experimental colitis. Here, we provide results of a phase 1 clinical, open-label, dose-escalation study of GED0301 in patients with active, steroid-dependent/resistant CD, aimed at assessing the safety and tolerability of the drug. Patients were allocated to three treatment groups receiving oral GED0301 once daily for 7 days at doses of 40, 80, or 160 mg. A total of 15 patients were enrolled. No serious adverse event was registered. GED0301 was well tolerated and no patient dropped out during the study. Twenty-five adverse events were documented in 11 patients, the majority of whom were judged to be of mild intensity and unrelated to treatment. GED0301 treatment reduced the percentage of inflammatory cytokine-expressing CCR9-positive T cells in the blood. The study shows for the first time that GED0301 is safe and well tolerated in patients with active CD.

Crohn's disease: A comparative prospective study of transabdominal ultrasonography, small intestine contrast ultrasonography, and small bowel enema

Background: Small intestine contrast ultrasonography (SICUS), when performed after distention of the small bowel lumen with an iso‐osmolar polyethylene glycol electrolyte‐balanced solution, shows high sensitivity (100%) and specificity (97%) in detecting small bowel abnormalities in patients who have not received a diagnosis but in whom there is a suspicion of intestinal diseases. The diagnostic yield of SICUS remains to be established in detecting small bowel lesions in patients with proven Crohns disease (CD) in comparison with transabdominal ultrasonography (TUS), and in relationship to the experience of the operator, using small bowel enema (SBE) as the “gold standard.” Aim: The aim of this study was to evaluate the diagnostic value of SICUS, when performed by a sonologist with 1 year of experience, and TUS, when performed by a sonologist with 10 years of experience, compared to SBE in the assessment of the site, extension, and stenosis of small intestinal lesions in CD patients. Patients and Methods: A total of 28 consecutive patients (men, 16; women, 12; age range, 21 to 60 yr) with a diagnosis of CD underwent TUS and SICUS, which were performed by 2 sonologists who were unaware of the radiologic findings, on the same day. SICUS was performed after the ingestion of 375 mL of a polyethylene glycol contrast solution. A standard SBE was performed on a different day by an expert radiologist who was unaware of the sonographic findings. Results: Sensitivities in the detection of small bowel lesions were 96% for TUS and 100% for SICUS. Compared with SBE, SICUS detected the presence of 4 lesions in the jejunum that had been missed by TUS. The mean (±SD) extent of the ileal disease was 22 ± 12.5 cm when measured during SBE, 14.5 ± 8.6 cm when measured during TUS, and 19.5 ± 12.5 cm when measured during SICUS [P = 0.05 (SICUS versus SBE)]. The correlation of the extension of the lesions between SICUS and SBE (r = 0.88) was better than that between TUS and SBE (r = 0.64). The sensitivities of TUS and SICUS in the detection of at least 1 stricture were 76% and 94%, respectively. Sensitivity and specificity in assessing prestenotic dilatation were 50% and 100%, respectively, at TUS, and 100% and 90%, respectively, at SICUS. Conclusion: In inexperienced hands, SICUS is a more accurate technique for assessing CD lesions, and the accuracy is better than that of TUS performed by an expert sonologist. The use of SICUS, instead of SBE, could be indicated for the follow‐up of patients with CD.

Small intestine contrast ultrasonography: an alternative to radiology in the assessment of small bowel disease.

Background: Radiology and transabdominal ultrasonography (TUS) are used in the evaluation of the small bowel; however, the former technique is limited by radiation exposure, and the latter by its inability to visualize the entire small bowel. Aim: To evaluate the diagnostic accuracy of small intestine contrast ultrasonography (SICUS) to assess the presence, number, site, and extension of small bowel lesions. Subjects and Methods: TUS, SICUS, and small bowel follow‐through (SBFT) were performed in 148 consecutive patients (78 women; age range, 12 to 89 yr), 91 with undiagnosed conditions, and 57 with previously diagnosed Crohns disease (CD). Results: In the undiagnosed patients, the sensitivity and specificity of TUS and SICUS were 57% and 100%, and 94.3% and 98%, respectively. In the CD patients, the sensitivity of TUS and SICUS was 87.3% and 98%, respectively. In comparison with SBFT, the extension of lesions was correctly assessed with SICUS and greatly underestimated with TUS. The concordance index between SBFT and SICUS for the number and site of lesions was 1 and 1 (P < 0.001), respectively, in undiagnosed patients, and 0.81 and 0.83 (P < 0.001), respectively, in CD patients. Between SBFT and TUS, the concordance index was 0.28 and 0.27 (not significant), respectively, in undiagnosed patients, and 0.28 and 0.31 (not significant), respectively, in CD patients. Conclusions: The diagnostic accuracy of SICUS is comparable to that of a radiologic examination, and is superior to that of TUS in detecting the presence, number, extension, and sites of small bowel lesions. These findings support the use of noninvasive SICUS for an initial investigation when small bowel disease is suspected and in the follow‐up of CD patients.

Treatment with biologic therapies and the risk of cancer in patients with IBD

The proven involvement of cytokines in the pathophysiology of IBD has led to the development of powerful, selective, anticytokine drugs—so-called biologics—as a therapy for IBD. Although the efficacy of infliximab, a chimeric monoclonal IgG1 antibody directed against tumor necrosis factor, is proven and the use of biologic agents is growing worldwide, there is concern about their long-term safety, which includes the risk of developing cancer. An increased risk of malignancies, particularly lymphoma, has been reported in some studies of infliximab-treated patients with IBD; however, the increased risk could be caused by the underlying chronic disease, severity of the disease, concomitant medications (e.g. conventional immunomodulators), infliximab itself, or all of these variables. At present, the data do not provide clear evidence for a causal association between infliximab and the increased cancer risk. In appropriately selected patients with severe, refractory Crohns disease, the benefits of biologic therapy seem to outweigh the cancer risk. Multicenter, case–control studies in large populations, with a long-term follow-up are needed to define the outcome of patients with IBD treated with biologic therapies.

Frequency, Pattern, and Risk Factors of Postoperative Recurrence of Crohn’s Disease After Resection Different from Ileo-Colonic

BackgroundThe frequency of recurrence in Crohn’s disease (CD) patients after curative resection different from the ileo-colonic is undefined. We aimed to assess the frequency, pattern, outcome, and risk factors of postoperative recurrence in CD patients under regular follow-up after anastomosis different from ileo-colonic.Materials and MethodsIn a retrospective study, clinical records of 537 CD patients under regular follow-up from January 2001 to August 2007 were reviewed. The outcome after surgery was assessed on the basis of clinical records prospectively recorded.ResultsPrevious resection was observed in 183 of 537 (34%) patients, including the ileo-colon in 145 (79%) and other gastrointestinal (GI) segments in 38 (21%). Recurrence was detected in 16 of 38 (42%) patients (all symptomatic) including five of 14 (35%) with ileostomy, five of five (100%) with ileo-rectal, three of 11 (27%) with ileo-ileal, one or four (25%) with colorectal, and two of three (33%) with duodenum-jejunal anastomosis. Ileo-colonic resection was reported in 145 of 183 (79%) patients, showing recurrence in 128 (88.3%) and symptomatic in 47 (36.7%) patients. The frequency of recurrence was higher in patients with ileo-colonic resection than in patients with other types of resection (128/145, 88% vs 16/38, 42%, p < 0.001). The frequency of symptomatic recurrence was lower in patients with ileo-colonic resection than in those with other resections (47/128, 37% vs 16/16, 100%; p < 0.001). Risk factors for recurrence were comparable in the two subgroups (smoke, odds ratio, OR 1.5 vs 1.4; appendectomy, OR 0.32 vs 0.33; familial inflammatory bowel disease, OR 0.43 vs 1.26). ConclusionsPostoperative recurrence is observed in a high proportion of CD patients after resection different from ileo-colon (including ileostomy), although at a lower frequency than observed after ileo-colonic resection.

A phase 1 open-label trial shows that smad7 antisense oligonucleotide (GED0301) does not increase the risk of small bowel strictures in Crohn's disease

In Crohns disease (CD), knockdown of Smad7, an inhibitor of Transforming Growth Factor (TGF)‐β1 activity, with a specific antisense oligonucleotide (GED0301) seems to be safe and tolerable and associates with TGF‐β1‐mediated suppression of inflammatory pathways.

Distinct Profiles of Effector Cytokines Mark the Different Phases of Crohn’s Disease

Objective Crohn’s Disease (CD)-associated inflammation is supposed to be driven by T helper (Th)1/Th17 cell-derived cytokines, even though there is evidence that the mucosal profile of cytokine may vary with the evolution of the disease. We aimed at comparing the pattern of effector cytokines in early and established lesions of CD. Design Mucosal samples were taken from the neo-terminal ileum of CD patients undergoing ileocolonic resection, with (early lesions) or without post-operative recurrence, and terminal ileum of CD patients with long-standing disease undergoing intestinal resection (established lesions). Inflammatory cell infiltrate was examined by immunofluorescence and cytokine expression was analysed by real-time PCR, flow-cytometry and ELISA. Results Before the appearance of endoscopic lesions, the mucosa of the neo-terminal ileum contained high number of T cells and macrophages, elevated levels of Th1-related cytokines and TNF-α and slightly increased IL-17A expression. Transition from this stage to endoscopic recurrence was marked by abundance of Th1 cytokines, marked increase in IL-17A, and induction of IL-6 and IL-23, two cytokines involved in the control of Th17 cell responses. In samples with established lesions, there was a mixed Th1/Th17 response with no TNF-α induction. Expression of IL-4 and IL-5 was up-regulated in both early and established lesions even though the fraction of IL-4-producing cells was lower than that of cells producing either interferon-γ or IL-17A. Conclusions Distinct mucosal profiles of cytokines are produced during the different phases of CD. A better understanding of the cytokines temporally regulated in CD tissue could help optimize therapeutic interventions in CD.

Efficacy and safety of infliximab and adalimumab in Crohn's disease: a single centre study.

Infliximab and adalimumab are highly effective in Crohns Disease (CD). This is supported by clinical trials and open‐label studies using either infliximab or adalimumab, thus not allowing a proper comparison between these anti‐TNFs in CD.

Cancer in Crohn's Disease patients treated with infliximab: A long-term multicenter matched pair study

Background: The long‐term risk of neoplasia in Crohns disease (CD) patients treated with infliximab is undefined. The aim was to assess, in a multicenter, matched‐pair study, whether infliximab use in CD is associated with an increased frequency of neoplasia in the long term. Methods: A multicenter, long‐term, matched‐pair study was conducted in 12 referral inflammatory bowel disease (IBD) centers. An initial cohort of 808 CD patients, including 404 infliximab‐treated (CD‐IFX) and 404 matched CD controls never treated with infliximab (CD‐C) studied from 1999 to 2004, was followed up for an additional 4 years (2004–2008). Cases and controls were matched for: sex, age (±5 years), CD site, follow‐up (±5 years), immunosuppressant use, and CD duration (±5 years). From 1999 to 2008 the frequency and characteristics of neoplasia were compared between CD‐IFX and CD‐C. Results: In 2008, 591 patients (304 CD‐IFX, 287 CD‐C) were in follow‐up. Matched couples included 442 patients: 221 CD‐IFX and 221 CD‐C (median follow‐up, months: 72, range 48–114 versus 75, range 44–114). From 1999 to 2008 the frequency of neoplasia among the 591 patients did not differ between CD‐IFX (12/304; 3.94%) and CD‐C (12/287; 4.19%; P = 0.95). A comparable frequency of neoplasia was also observed between the 221 matched couples (CD‐IFX: 8/221; 3.61% versus CD‐C: 9/221; 4.07%; P = 1). No specific histotype of cancer appeared associated with infliximab use. Conclusions: The frequency of neoplasia was comparable in an adult population of CD patients treated or not with infliximab, matched for clinical variables and followed up for a median of 6 years. (Inflamm Bowel Dis 2011)