Corticosteroids and Mesalamine Versus Corticosteroids for Acute Severe Ulcerative Colitis: A Randomized Controlled Trial.

BACKGROUND & AIMS: Corticosteroids are the mainstay of treatment for hospitalized patients with acute severe ulcerative colitis (ASUC). However, whether the addition/continuation of mesalamine with corticosteroids during hospitalization is superior to corticosteroids alone is unknown. METHODS: This was a randomized controlled, investigator-blinded, clinical trial conducted in 10 centers in 7 countries. Patients hospitalized with ASUC (Lichtiger score ≥10) were eligible. Patients received corticosteroids alone or corticosteroid + mesalamine (4 g/day mesalamine) by a stratified randomization according to mesalamine use before admission. The primary outcome was the percentage of patients who responded to treatment by day 7, defined by a drop >3 points in the Lichtiger score and an absolute score <10 without the need for rescue medications or colectomy. RESULTS: Three hundred forty-six patients were screened, and 149 were included (70/149 female; median age, 41 years). Of these, 73 received corticosteroids + mesalamine, and 76 received corticosteroids alone. For the primary outcome, 53 of 73 patients (72.6%) receiving corticosteroids with mesalamine responded versus 58 of 76 patients (76.3%) on corticosteroids alone (odds ratio, 0.82; 95% confidence interval, 0.39-1.72; P = .60). There was no difference between groups in duration of hospitalization, C-reactive protein normalization rate, or colectomy rate up to day 90. The need for biologics among patients receiving combination of corticosteroids with mesalamine was numerically lower by day 30 (P = .11) and day 90 (P = .07). CONCLUSIONS: In this randomized controlled trial, combination of mesalamine with corticosteroids did not benefit hospitalized patients with ASUC more than corticosteroids alone. An exploratory signal for a reduced need for biologics at 90 days in the mesalamine group merits further evaluation. CLINICALTRIALS: gov ID: NCT01941589.

Chromoendoscopy or white light endoscopy for neoplasia detection in Lynch syndrome, a meta-analysis.

BACKGROUND: Lynch syndrome carries an increased risk of colorectal neoplasia, hence annual surveillance colonoscopy is recommended. This study aimed to compare the diagnostic yields of image enhancement modalities for colorectal neoplasia in patients with Lynch syndrome. METHODS: Meta-analysis of pooled ratios of lesion detection rates (RRs) and odds ratios (ORs) with 95% confidence intervals (CIS), comparing white light endoscopy (WLE) and chromoendoscopy (ChE). RESULTS: Four studies comparing WLE to ChE were analyzed. ChE fared better than WLE in overall lesion detection (RR 1.97, 95% CI 1.63-2.38) and detection of adenomas (RR 1.53, 95% CI 1.07-2.17), flat lesions (RR 3.4, 95% CI 2.47-4.67) and proximally-located lesions (RR 2.93, 95% CI 1.91-4.5). The odds of a patient having any lesion found were higher in ChE compared to WLE (OR 2.42, 95% CI 1.56-3.75). The odds of a patient having adenoma(s) found on endoscopy were not significantly higher in chromoendoscopy compared to white light endoscopy (OR 1.81, 95% CI 0.65-5.01). CONCLUSION: Using standard definition technology, ChE allows detection of more lesions, especially adenomas, flat lesions and proximal lesions in Lynch syndrome patients, compared to WLE. The results show that surveillance colonoscopy of Lynch syndrome patients should be performed using ChE.

Prospective Observational Evaluation of Time-Dependency of Adalimumab Immunogenicity and Drug Concentrations: The POETIC Study.

OBJECTIVES: Adalimumab is usually self-injected at home, making prospective serial-sampling studies challenging and scarce. This has led to a gap in knowledge about evolution of anti-adalimumab antibodies (AAAs) over time and its correlation with clinical and inflammatory outcomes. METHODS: A program for home visits by physicians at induction, every 3 months and at event of relapse, was established prospectively for Crohn's disease (CD) patients. At each visit, patients' clinical scores were determined and sera were obtained for C-reactive protein, drug, and AAA levels. This cohort was compared to a parallel prospective cohort of infliximab-treated CD patients. In a subgroup of 29 patients, trough and in-between-trough levels were compared, to elucidate the importance of timing of sampling during the injection cycle. RESULTS: Ninety-eight CD patients starting adalimumab were prospectively followed (median follow-up 44 weeks) and 621 serum samples were analyzed. Thirty-three patients (32%) developed AAA; 18/33 (55%) of them as early as week 2, and 26/33 (79%) by week 14. Induction period AAAs were strongly associated with primary non-response (odds ratio (OR) = 5.4, 95% confidence interval (CI): 1.6-17.8, p = 0.005). As compared to antibodies-to-infliximab (ATI), AAA formation rate over time was significantly lower (p = 0.01) and AAA were much more specific-85% of AAA events were associated with loss-of-response compared with 58% rate for ATI (p = 0.01). In 29 patients sampled serially during an injection cycle, levels of drug and AAA seemed comparable between four time-points during a single cycle both in patients with or without AAA (n = 8, n = 21, respectively). CONCLUSIONS: When followed prospectively and serially, AAAs are found to arise earlier than previously appreciated and their impact may be more pronounced for primary rather than secondary, non-response. Drug and AAA levels were similar both at trough and in-between injections, enabling to simplify therapeutic drug monitoring of adalimumab.

Capsule Endoscopy, Magnetic Resonance Enterography, and Small Bowel Ultrasound for Evaluation of Postoperative Recurrence in Crohn's Disease: Systematic Review and Meta-Analysis.

Background: Anastomotic recurrence is frequent in patients with Crohn's disease (CD) following ileocecal resection. The degree of endoscopic recurrence, quantified by the Rutgeerts score (RS), is correlated with the risk of clinical and surgical recurrence. Noninvasive modalities such as capsule endoscopy (CE), magnetic resonance enterography (MRE), and intestinal ultrasound (US) may yield similar information without the need for ileocolonoscopy (IC). The aim of our meta-analysis was to evaluate the accuracy of those modalities for detection of endoscopic recurrence in postoperative CD patients. Methods: We performed a systematic literature search for studies comparing the accuracy of CE, MRE, and US with IC for detection of postoperative recurrence in CD. We calculated pooled diagnostic sensitivity, specificity, diagnostic odds ratio (DOR), and area under the curve (AUC) for each comparison. Results: A total of 135 studies were retrieved; 14 studies were eligible for analysis. For CE, the pooled sensitivity was 100% (95% CI, 91%-100%), specificity was 69% (95% CI, 52%-83%), DOR was 30.8 (95% CI, 6.9-138), and AUC was 0.94. MRE had pooled sensitivity of 97% (95% CI, 89%-100%), specificity of 84% (95% CI, 62%-96%), DOR of 129.5 (95% CI, 16.4-1024.7), and AUC of 0.98. US had pooled sensitivity of 89% (95% CI, 85%-92%), specificity of 86% (95% CI, 78%-93%), DOR of 42.3 (95% CI, 18.6-96.0), and AUC 0.93. Conclusions: CE, MRE, and US provide accurate assessment of postoperative endoscopic recurrence in CD. These modalities should gain wider use for detection of postoperative recurrence; the prognostic value of those diagnostic findings merits evaluation in further prospective studies.

Chromoendoscopy, Narrow-Band Imaging or White Light Endoscopy for Neoplasia Detection in Inflammatory Bowel Diseases.

BACKGROUND: Studies have confirmed an increased risk of colorectal cancer in patients with ulcerative colitis; hence, surveillance is recommended. Optional modalities include white light endoscopy (WLE) or dye-spray chromoendoscopy. However, narrow-band imaging (NBI) is still not considered comparable to chromoendoscopy. AIM: The aim of this study was to compare the diagnostic yield (DY) of WLE, chromoendoscopy, NBI for detection of neoplasia in patients with inflammatory bowel disease (IBD) by performing a meta-analysis of the existing literature. METHODS: We searched databases for prospective studies. For each modality, we performed comparative per-lesion analysis (any neoplasia detection) and per-patient analysis (patient with neoplastic lesions). Meta-analysis was performed using fixed-effect model unless heterogeneity was high. Odds ratios (ORs) with 95% CIs were calculated and pooled. RESULTS: Five studies compared chromoendoscopy to WLE. Chromoendoscopy (n = 361) was superior to WLE (n = 358) with per-patient analysis OR 2.05 (95% CI 1.26, 3.35) and per-lesion analysis OR 2.79 (95% CI 2.08, 3.73). High-definition (HD) chromoendoscopy was superior to HD-WLE with per-lesion analysis OR 2.48 (95% CI 1.55, 3.97). In four studies comparing NBI to WLE (n = 305), no difference was found in per-patient analysis OR 0.97 (95% CI 0.62, 1.53) and per-lesion analysis OR 0.94 (95% CI 0.63, 1.4). In two studies comparing CE to NBI (n = 104), no difference was found in per-patient analysis OR 1.0 (95% CI 0.51, 1.95) and per-lesion analysis OR 1.29 (95% CI 0.69, 2.41). CONCLUSION: Chromoendoscopy is superior to WLE for detection of dysplasia in IBD, even with HD endoscopy. No difference in DY could be demonstrated for NBI in comparison with other modalities.

Impact of Infliximab and Cyclosporine on the Risk of Colectomy in Hospitalized Patients with Ulcerative Colitis Complicated by Cytomegalovirus-A Multicenter Retrospective Study.

BACKGROUND: Cytomegalovirus (CMV) is frequently detected in patients with ulcerative colitis (UC). The impact of CMV infection on the outcome of UC exacerbation remains unclear. The benefit of combining antiviral with anti-inflammatory treatment has not been evaluated yet. The aim of this study was to compare the outcome of CMV-positive hospitalized patients with UC treated with antiviral therapy either alone or combined with salvage anti-inflammatory therapy (infliximab [IFX] or cyclosporine A [CsA]). METHODS: This was a multicenter retrospective study of hospitalized CMV-positive patients with UC. The patients were classified into 2 groups: antiviral-if treated with antivirals alone; combined-if treated with both antiviral and anti-inflammatory therapy. The outcomes included the rate of colectomy in both arms during the course of hospitalization and after 3/12 months. RESULTS: A total of 110 patients were included; 47 (42.7%) patients did not receive IFX nor CsA; 36 (32.7%) received IFX during hospitalization or within 1 month before hospitalization; 20 (18.1%) patients received CsA during hospitalization; 7 (6.4%) were exposed to both IFX and CsA. The rate of colectomy was 14.5% at 30 days, 20.0% at 3 months, and 34.8% at 12 months. Colectomy rates were similar across treatment groups. No clinical and demographic variables were independently associated with the risk of colectomy. CONCLUSIONS: IFX or cyclosporine therapy is not associated with additional risk for colectomy over antiviral therapy alone in hospitalized CMV-positive patients with UC.

Combination of corticosteroids and 5-aminosalicylates or corticosteroids alone for patients with moderate-severe active ulcerative colitis: A global survey of physicians' practice.

AIM: To examine treatment decisions of gastroenterologists regarding the choice of prescribing 5-aminosalycilates (5ASA) with corticosteroids (CS) versus corticosteroids alone for patients with active ulcerative colitis (UC). METHODS: A cross-sectional questionnaire exploring physicians' attitude toward 5ASA + CS combination therapy vs CS alone was developed and validated. The questionnaire was distributed to gastroenterology experts in twelve countries in five continents. Respondents' agreement with stated treatment choices were assessed by standardized Likert scale. Background professional characteristics of respondents were analyzed for correlation with responses. RESULTS: Six hundred and sixty-four questionnaires were distributed and 349 received (52.6% response rate). Of 340 eligible respondents, 221 (65%) would continue 5ASA in a patient hospitalized for intravenous CS treatment due to a moderate-severe UC flare, while 108 (32%) would stop the 5ASA (P < 0.001), and 11 (3%) are undecided. Similarly, 62% would continue 5ASA in an out-patient starting oral CS. However, only 140/340 (41%) would proactively start 5ASA in a hospitalized patient not receiving 5ASA before admission. Most (94%) physicians consider the safety profile of 5ASA as very good. Only 52% consider them inexpensive, 35% perceive them to be expensive and 12% are undecided. On multi-variable analysis, less years of practice and perception of a plausible additive mechanistic effect of 5ASA + CS were positively associated with the decision to continue 5ASA with CS. CONCLUSION: Despite the absence of data supporting its benefit, most gastroenterologists endorse combination of 5ASA + CS for patients with active moderate-to-severe UC. Randomized controlled trials are needed to assess if 5ASA confer any benefit for these patients.

Diagnostic yield of capsule endoscopy versus magnetic resonance enterography and small bowel contrast ultrasound in the evaluation of small bowel Crohn's disease: Systematic review and meta-analysis.

BACKGROUND AND AIMS: Capsule endoscopy (CE), magnetic resonance enterography (MRE) and small bowel (SB) intestinal contrast ultrasound (SICUS) are the modalities of choice for SB evaluation. This study aimed to compare the diagnostic yield (DY) of CE to MRE and SICUS in detection and monitoring of SB CD through meta-analysis of the available literature. METHODS: We performed a systematic literature search for trials comparing the accuracy of CE, MRE and SICUS for detection of active SB inflammation in patients with suspected and/or established CD. Only prospective studies comparing CE with another additional diagnostic modality were included in the final analysis. Pooled odds ratios (ORs) for the DY of the three modalities were calculated. RESULTS: A total of 112 studies were retrieved; following selection, 13 studies were eligible for analysis. The DY of CE for detection of active SB CD was similar to that of MRE (10 studies, 400 patients, OR 1.17; 95% CI 0.83-1.67) and SICUS (5 studies, 142 patients, OR 0.88; 95% CI 0.51-1.53). The outcomes were similar for the subgroups of suspected versus established CD and adult versus pediatric patients. CE was superior to MRE for proximal SB CD (7 studies, 251 patients, OR 2.79; 95% CI 1.2-6.48); the difference vs SICUS was not significant. CONCLUSION: CE, MRE and SICUS have similar DY for detection of SB CD in both suspected and established CD. CE is superior to MRE for detection of proximal SB disease, however the risk of capsule retention should be considered.

Bowel preparation in "real-life" small bowel capsule endoscopy: a two-center experience.

BACKGROUND: Video capsule endoscopy (VCE) is an established diagnostic tool for the investigation of small bowel (SB) pathology. Bowel preparation prior to VCE may improve visualization, transit time, and diagnostic yield. We aimed to evaluate the "real-life" experience comparing two different preparation protocols in patients undergoing SB VCE. METHODS: We performed a retrospective analysis of prospectively collected data from SB VCE procedures, performed in two tertiary care medical centers in Israel. VCE procedures performed at "Sheba Medical Center" used a 2-L polyethylene glycol (PEG) bowel preparation (n=360) while VCEs performed at "Rambam Health Care campus" used a clear liquid diet plus 12-h fast protocol (n=500). A dichotomous preparation scale (adequate, inadequate) was used to classify cleansing quality. Data collection included patient and procedural details. The proportion of VCE procedures with adequate bowel preparation and the overall positive SB findings in the two different bowel preparation protocols were evaluated. RESULTS: SB completion rates were higher in the PEG protocol (96% vs. 83%, P<0.001) and SB passage time was significantly faster in the PEG protocol (mean 217±73 vs. 238±77 min, P<0.001). Bowel preparation quality was similar between groups (8% vs. 7% inadequate preparation, P=0.591). Overall positive SB findings were similar between the two groups (57% clear liquid fasting only vs. 51% PEG protocol, P=0.119). CONCLUSION: In this large cohort, a 2-L PEG protocol had similar preparation quality and diagnostic yield compared with clear liquid fasting.

Combination of Corticosteroids with 5-Aminosalicylic Acids Compared to Corticosteroids Alone for Hospitalized Patients with Active Ulcerative Colitis.

BACKGROUND: Although 5-amino-salycilic acids (5-ASA) are often used with corticosteroid treatment in moderate-to-severe ulcerative colitis, the value of continuing/initiating 5-ASA in this clinical setting has not been explored. OBJECTIVES: To investigate the impact of a combination 5-ASA+corticosteroid therapy on the outcome of hospitalized patients with acute moderate-severe ulcerative colitis. METHODS: We conducted a retrospective study of patients hospitalized with moderate-severe ulcerative colitis in two centers, Israel and South Korea. Patients were classified into those who received 5-ASA and corticosteroids and those who received corticosteroids alone. Analysis was performed for each hospitalization event. The primary outcome was the rate of treatment failure defined as the need for salvage therapy (cyclosporin-A/infliximab/colectomy). The secondary outcomes were 30 days re-admission rates, in-hospital mortality rates, time to improvement, and length of hospitalization. RESULTS: We analyzed 209 hospitalization events: 151 patients (72%) received 5-ASA+corticosteroids and 58 (28%) corticosteroids alone. On univariate analysis the combination therapy group had a lower risk for treatment failure (11% vs. 31%, odds ratio 0.28, 95% confidence interval 0.13-0.59, P = 0.001). However, this difference disappeared on multivariate analysis, which showed pre-admission oral corticosteroid treatment to be the most significant factor associated with the need for salvage therapy. CONCLUSIONS: A signal for possible benefit of a combination 5-ASA and corticosteroids therapy was found, but was confounded by the impact of pre-admission corticosteroid treatment.

Curcumin in Combination With Mesalamine Induces Remission in Patients With Mild-to-Moderate Ulcerative Colitis in a Randomized Controlled Trial.

BACKGROUND & AIMS: The phytochemical compound curcumin was reported to be effective in maintaining remission in patients with ulcerative colitis (UC). We investigated curcumin's efficacy in inducing remission in patients with active mild-to-moderate UC. METHODS: We performed a multicenter randomized, placebo-controlled, double-blind study of 50 mesalamine-treated patients with active mild-to-moderate UC (defined by the Simple Clinical Colitis Activity Index [SCCAI]) who did not respond to an additional 2 weeks of the maximum dose of mesalamine oral and topical therapy. Patients were randomly assigned to groups who were given curcumin capsules (3 g/day, n = 26) or an identical placebo (n = 24) for 1 month, with continued mesalamine. The primary outcome was the rate of clinical remission (SCCAI ≤2) at week 4. Clinical and endoscopic responses were also recorded. RESULTS: In the intention-to-treat analysis, 14 patients (53.8%) receiving curcumin achieved clinical remission at week 4, compared with none of the patients receiving placebo (P = .01; odds ratio [OR], 42; 95% confidence interval [CI], 2.3-760). Clinical response (reduction of ≥3 points in SCCAI) was achieved by 17 patients (65.3%) in the curcumin group vs. 3 patients (12.5%) in the placebo group (P < .001; OR, 13.2; 95% CI, 3.1-56.6). Endoscopic remission (partial Mayo score ≤1) was observed in 8 of the 22 patients evaluated in the curcumin group (38%), compared with none of 16 patients evaluated in the placebo group (P = .043; OR, 20.7; 95% CI, 1.1-393). Adverse events were rare and comparable between the 2 groups. CONCLUSIONS: Addition of curcumin to mesalamine therapy was superior to the combination of placebo and mesalamine in inducing clinical and endoscopic remission in patients with mild-to-moderate active UC, producing no apparent adverse effects. Curcumin may be a safe and promising agent for treatment of UC. Clinicaltrials.gov number: NCT01320436.

Recurrent small bowel obstruction in a 60-year-old celiac patient: a rare entity of a common disease.

A 60-year-old woman with a medical history of celiac disease was evaluated due to recurrent episodes of small bowel obstruction. Upper and lower endoscopies were normal. The small bowel pathology consisted of celiac disease, and the anti-endomysial antibody was positive. Dilatation of small bowel loops was demonstrated on abdominal computed tomography. Further evaluation was conducted using video capsule endoscopy that demonstrated regional narrowing and severe ulceration in the middle of the small bowel. Upper and lower double balloon endoscopies failed to demonstrate the lesion. On explorative laparotomy a small bowel mass in the proximal ileum was excised. Pathology revealed ulcerated, well to moderately differentiated adenocarcinoma without regional nodal involvement. We discuss the etiology and treatment of small bowel carcinoma. This case emphasizes that a high level of suspicion is required in order to diagnose early stage small bowel adenocarcinoma in celiac patients.

PillCam small bowel capsule endoscopy gastric passage interval association with patient's complaints and pathological findings: a prospective study.

BACKGROUND AND AIMS: Prolonged gastric transit interval of small bowel video capsule endoscopy (SBCE) can potentially indicate a motility disorder and disrupt whole small bowel visualization. The aim of this study was to prospectively examine the association of prolonged gastric passage interval with symptoms, anthropometric and laboratory factors, and factors related to the SBCE examination, such as indications and pathological findings. MATERIALS AND METHODS: This was a prospective single-center study that included 100 patients who underwent SBCE for any indication. Before the examination, clinical, demographic, and anthropometric data were recorded. The patients filled the Gastroparesis Cardinal Symptoms Index (GCSI) questionnaire. We assessed the difference in the study parameters between the prolonged gastric transit (≥45 min) group and the group with a normal gastric transit. RESULTS: Seventy-six patients had normal gastric passage interval and 24 patients had prolonged gastric passage interval. No significant differences were found between the groups in age, sex, prevalence of diabetes mellitus, use of antimotility drugs, indications for the exam and levels of hemoglobin, C-reactive protein, and albumin. Esophageal and small bowel transition intervals did not vary between both groups. The mean score for any GCSI item and the mean total GCSI score did not differ significantly between the normal and the prolonged gastric passage interval groups. There were no significant differences between the groups in pathological findings in the small bowel. CONCLUSION: In the study population, prolonged SBCE gastric transit interval had no clinical significance, and therefore, probably does not mandate any further gastrointestinal evaluation.

The temporal evolution of antidrug antibodies in patients with inflammatory bowel disease treated with infliximab.

OBJECTIVE: To characterise the temporal evolution of antibodies to infliximab (ATI). DESIGN: Prospective observational study of infliximab-treated patients with inflammatory bowel disease between 2009 and 2012. INTERVENTIONS: Trough levels of infliximab and ATI were measured before each infusion by anti-λ ELISA. Patients were monitored for disease activity by clinical activity indexes and for dose-intensification or infliximab cessation. The occurrence of transient ATI disappearing spontaneously without intervention was recorded separately. RESULTS: 125 patients were included (98 Crohn's disease, 27 ulcerative colitis, median follow-up 11.5±22 months) and 1119 sera were analysed for infliximab and ATI levels. Kaplan-Meier analysis showed that 42% of patients remained ATI-free by 4 years of treatment. Most (90%) of the patients who developed ATI did so within the first 12 months of therapy, whereas transient ATI were detected throughout the duration of infliximab therapy (p<0.001). ATI incidence was similar between patients who received infliximab previously (episodic/interrupted therapy patients, n=14) and scheduled-therapy patients (n=111). In the scheduled group, combination immunomodulator+infliximab resulted in longer ATI-free survival compared with monotherapy (p=0.003, logrank test). Survival free of clinical loss of response was enjoyed by 51% of patients, and serial measurements showed that ATI development often preceded the onset of clinical flare. CONCLUSIONS: When followed prospectively, most patients who develop ATI do so within the first 12 months of therapy. This incidence is reduced by concomitant immunomodulator even in scheduled-therapy patients. In contrast, transient ATI, which are of little clinical significance, can appear haphazardly at any time during treatment. The onset of clinical loss of response may lag behind the appearance of anti-infliximab antibodies.

Curcumin inhibits hepatitis B virus via down-regulation of the metabolic coactivator PGC-1alpha.

Hepatitis B virus (HBV) infects the liver and uses its cell host for gene expression and propagation. Therefore, targeting host factors essential for HBV gene expression is a potential anti-viral strategy. Here we show that treating HBV expressing cells with the natural phenolic compound curcumin inhibits HBV gene expression and replication. This inhibition is mediated via down-regulation of PGC-1alpha, a starvation-induced protein that initiates the gluconeogenesis cascade and that has been shown to robustly coactivate HBV transcription. We suggest curcumin as a host targeted therapy for HBV infection that may complement current virus-specific therapies.

The "Trojan horse" model-delivery of anti-HBV small interfering RNAs by a recombinant HBV vector.

Hepatitis B virus (HBV) is a small virus that infects the liver. The major obstacle in applying the RNA interference method as an anti-HBV weapon is the challenge to deliver the small interfering RNA molecules to the liver efficiently and specifically. Here we show that HBV-specific short hairpin RNAs (shRNAs) are efficiently expressed from a recombinant HBV into which an shRNA-expressing cassette was inserted, resulting in a significant knock-down of HBV gene expression. Notably, this recombinant HBV still expresses the HBV Core protein, which is targeted by the shRNAs produced by the same vector. Our results set the stage for further use of this recombinant HBV virus with the potential to function as a "Trojan horse"; one that specifically targets the liver and uses the resident virus as an helper for its own propagation, and at the same time eliminate itself and the resident HBV by knocking-down their gene expression.