Maria Laura Annunziata

Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis

The inhibitory effects of vitamin D on colitis have been previously documented. Global vitamin D receptor (VDR) deletion exaggerates colitis, but the relative anticolitic contribution of epithelial and nonepithelial VDR signaling is unknown. Here, we showed that colonic epithelial VDR expression was substantially reduced in patients with Crohns disease or ulcerative colitis. Moreover, targeted expression of human VDR (hVDR) in intestinal epithelial cells (IECs) protected mice from developing colitis. In experimental colitis models induced by 2,4,6-trinitrobenzenesulfonic acid, dextran sulfate sodium, or CD4(+)CD45RB(hi) T cell transfer, transgenic mice expressing hVDR in IECs were highly resistant to colitis, as manifested by marked reductions in clinical colitis scores, colonic histological damage, and colonic inflammation compared with WT mice. Reconstitution of Vdr-deficient IECs with the hVDR transgene completely rescued Vdr-null mice from severe colitis and death, even though the mice still maintained a hyperresponsive Vdr-deficient immune system. Mechanistically, VDR signaling attenuated PUMA induction in IECs by blocking NF-κB activation, leading to a reduction in IEC apoptosis. Together, these results demonstrate that gut epithelial VDR signaling inhibits colitis by protecting the mucosal epithelial barrier, and this anticolitic activity is independent of nonepithelial immune VDR actions.

The PROSIT-BIO Cohort: A Prospective Observational Study of Patients with Inflammatory Bowel Disease Treated with Infliximab Biosimilar.

Background: Few data are available on the safety and efficacy of infliximab biosimilar CT-P13 in patients with ulcerative colitis and Crohns disease. Methods: A prospective, multicenter, cohort study using a structured database. Results: Consecutive patients (313 Crohns disease and 234 ulcerative colitis) were enrolled from 31 referral centers; 311 patients were naive to anti–tumor necrosis factor alpha, 139 had a previous exposure to biologics, and the remaining 97 were switched to CT-P13 after a mean of 18 ± 14 infusions of infliximab. The mean follow-up was 4.3 ± 2.8 months, and the total follow-up time was 195 patient-years. After 2061 infusions, 66 serious adverse events were reported (12.1%), 38 (6.9%) of them were infusion-related reactions. The biosimilar had to be stopped in 29 (5.3%) cases for severe infusion reactions (8 naive, 19 previous exposed, and 2 switch), and in further 16 patients (2.9%) for other serious adverse events. Infusion reactions were significantly more frequent in patients pre-exposed to infliximab than to other anti–tumor necrosis factor alpha (incidence rate ratio = 2.82, 95% CI: 1.05–7.9). The efficacy of the biosimilar was evaluated in 434 patients who received treatment for at least 8 weeks, using time-to-event methods for censored observations: 35 patients were primary failures (8.1%). After further 8, 16, and 24 weeks, the efficacy estimations were 95.7%, 86.4%, and 73.7% for naive, 97.2%, 85.2%, and 62.2% for pre-exposed, and 94.5%, 90.8%, and 78.9% for switch, respectively (log-rank P = 0.64). Conclusions: Although no direct comparison was performed, preliminary data on efficacy and safety of CT-P13 were in line with those of infliximab.

Mucosal healing is associated with improved long-term outcome of maintenance therapy with natalizumab in Crohn's disease

Background:Natalizumab is an efficacious agent for induction and maintenance of remission in patients with Crohns disease (CD) who have failed anti–tumor necrosis factor agents. We aimed to assess the impact of endoscopic severity and mucosal healing on the long-term outcome of natalizumab treatment in CD. Methods:We retrospectively assessed endoscopic severity according to the Simple Endoscopic Score for Crohns Disease in patients with CD who received natalizumab therapy. The degree of endoscopic severity before natalizumab treatment and mucosal healing after treatment and their correlation with long-term outcome were studied. Results:Thirty-two patients with CD (15 male, median age 32.5 years) receiving natalizumab underwent at least 1 colonoscopy before or during natalizumab treatment. All patients had previously failed immunomodulator(s), and 31 failed anti–tumor necrosis factor agent(s). Mean duration of natalizumab treatment was 14.1 months. Baseline Simple Endoscopic Score for CD was categorized into quartiles, and those with a greater score were less likely to respond to treatment as assessed by Kaplan–Meier survival analysis (n = 32, log-rank test, P = 0.0055). Mucosal healing (decrease of Simple Endoscopic Score for CD of >70%) was achieved in 11 of 26 patients (42.3%), and this was correlated with an improved long-term outcome (log-rank test, P = 0.0063). Conclusions:The degree of endoscopic inflammation correlates to response to natalizumab and maintenance of remission. These findings provide prognostic information for patient management decisions.

Management of inflammatory bowel disease: past, present and future.

The inflammatory bowel diseases (IBD), ulcerative colitis (UC) and Crohn’s disease (CD), are chronic, progressive inflamma tory disorders of the GI tract. The pathogenesis of IBD involves environmental, genetic and immuno logical factors. The past decade has seen a great change in the medical management of IBD, largely owing to the progress in basic research that continues to unravel its pathogenesis. The current review will focus on the milestones in IBD management that have occurred in the past decade (present), in the preceding 30–40 years (past) and the next decade (future). Past Evidence for the pathogenesis of IBD

Can we treat ulcerative colitis with nutritional supplements

Mikhailova et al. report a multicentre, phase II, double-blind, placebo-controlled trial of propionyl-L-carnitine (PLC) in mild-to-moderate ulcerative colitis (UC) patients concomitant with other stable oral therapies. Two doses were compared with placebo. The primary end-point was the proportion of patients achieving clinical response at 4-weeks, defined as a decrease ‡3 from baseline in the disease activity index (DAI) score. The endpoint was achieved in 75%, 69% and 50% in the PLC 1 g ⁄ day, 2 g ⁄ day and placebo groups respectively. Although the combined PLC groups achieved response more often than placebo (P < 0.02), results were ‘driven’ by the PLC 1 g ⁄ day (and not 2 g ⁄ day) treatment, which was significant compared with placebo (P = 0.02). No significant differences in clinical remission or histological responses rates were observed amongst the treatment groups. However, when stratified by disease severity, those with mild disease in the 1 g ⁄ day group were significantly more likely than patients receiving placebo to experience clinical remission (P < 0.05). Due to the small number of patients with moderate disease, no statistical conclusions could be made. PLC treatment was well-tolerated and adverse events were mild and not significantly different between the PLC and placebo groups. An energy deficiency state of the intestinal mucosa, via reduction in butyrate oxidation, could be pathogenic for UC. Several experiments confirm the impact of short-chain fatty acids (SCFA) on colonic epithelium. However, clinical studies assessing either rectal administration of SCFA mixtures or butyrate provided inconsistent results. Among possible mechanisms leading to decreased SCFA oxidation during intestinal inflammation, a defect in SCFA transport has been described. In this setting, L-carnitine plays a major role in the oxidation of fatty acids. Most recently, attention towards L-carnitine in inflammatory bowel disease comes from studies implicating genetic polymorphisms in the carnitine organic cation transporter associated with the development of Crohn’s disease and UC. L-carnitine has a protective effect in gut inflammation in an experimental colitis in rats. In humans, rectal irrigation with PLC in inactive or mild distal UC led to histopathological improvement. Oral PLC in the Mikhailova study was administered as a new formulation, delivering active ingredient directly into the colonic lumen. In a very recent study M. L. Annunziata & S. Hanauer Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, The University of Chicago, Chicago, IL, USA. E-mail: shanauer@medicine.bsd. uchicago.edu

The PROSIT Cohort of Infliximab Biosimilar in IBD: A Prolonged Follow-up on the Effectiveness and Safety Across Italy

BACKGROUND We report a prospective, nationwide cohort evaluating the safety and effectiveness of CT-P13. METHODS A structured database was used to record serious adverse events (SAEs), clinical remission/response, inflammatory biomarkers (CRP and calprotectin), and endoscopic findings. RESULTS Eight hundred ten patients with inflammatory bowel disease (IBD) (452 Crohns disease [CD]) were enrolled. Four hundred fifty-nine patients were naïve to anti-TNFα (group A), 196 had a previous exposure (group B), and the remaining 155 were switched to CT-P13 (group C). All patients were included in the safety evaluation with a mean follow-up of 345 ± 215 days and a total number of 6501 infusions. One hundred fifty-four SAEs were reported (19%), leading to cessation of the biosimilar in 103 subjects (12.7%). Infusion reactions were 71, leading to cessation of the biosimilar in 53 subjects (6.5%), being significantly more frequent in patients pre-exposed to anti-TNFα (P = 0.017). The efficacy of therapy was calculated in 754 IBD patients, with a mean follow-up of 329 ± 202 days. Forty-eight patients had a primary failure (6.4%), and 188 (25.6%) lost response during follow-up. Six hundred twenty-eight (364 CD) and 360 IBD patients (222 CD) completed the follow-up at 6 and 12 months, respectively. At 12 months, patients without loss of response were 71%, 64%. and 82% in groups A, B, and C, respectively (log rank P = 0.01). Clinical/endoscopic scores and inflammatory biomarkers dropped significantly in CD and UC patients (P = 0.01 and P < 0.0001) compared with baseline. CONCLUSIONS In this large prospective cohort, no further signals of difference in safety and effectiveness of CT-P13 in IBD has been observed.

Tu1134 Layered Pattern of Enhancement and Retrodilation At Magnetic Resonance Enterography Predict the Outcome of Anti-TNF Alpha Therapy in Patients With Moderate-to-Severe Ileal Crohn's Disease

of 1-31. New/worse inflammation was found in 43.8% of CTs while any new/worse finding was found in 57.4%. PA+ occurred in 16.8% of CTs. Univariate analysis shows that younger and female patients were less likely to have I but not PA+. Steroid use did predict a higher probability of PA+ (OR 1.58, 95%CI 1.01-2.47) but not I (OR 1.01, 95%CI 0.70-1.44). Biologic agents and other immunosuppression did not predict either outcome. Among the labs, CRP was a good predictor of I and PA+ while ESR only predicted PA+. Higher absolute neutrophil count and lymphocyte count predicted both outcomes. The multivariable model for I had a c statistic of 0.68; a cutoff of 16% has a sensitivity of 99.6% and negative predictive value of 92.3%. The model for PA+ had better performance characteristics with a c statistic of 0.80; a cutoff of 5% has a sensitivity of 94.9% and a negative predictive value of 97.7%. Conclusions: Patients with CD are exposed to radiation frequently but have significant new/worse findings less than 60% of the time. Models with good negative predictive values predicting I and PA+ were identified. Automated use of these models could aid ER physicians in the decision to avoid CT scans in patients with low likelihood of a positive scan. Prospective studies are needed to validate these models and their utility in clinical practice.