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.

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.

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.

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.

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.

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.

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.

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.

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.