Prospective cohort study of appendicectomy for treatment of therapy-refractory ulcerative colitis.

INTRODUCTION: Appendicectomy may reduce relapses and need for medication in patients with ulcerative colitis, but long-term prospective data are lacking. This study aimed to analyse the effect of appendicectomy in patients with refractory ulcerative colitis. METHODS: In this prospective multicentre cohort series, all consecutive patients with refractory ulcerative colitis referred for proctocolectomy between November 2012 and June 2015 were counselled to undergo laparoscopic appendicectomy instead. The primary endpoint was clinical response (reduction of at least 3 points in the partial Mayo score) at 12 months and long-term follow-up. Secondary endpoints included endoscopic remission (endoscopic Mayo score of 1 or less), failure (colectomy or start of experimental medication), and changes in Inflammatory Bowel Disease Questionnaire (IBDQ) (range 32-224), EQ-5D™ and EORTC-QLQ-C30-QL scores. RESULTS: A total of 28 patients (13 women; median age 40·5 years) underwent appendicectomy. The mean baseline IBDQ score was 127·0, the EQ-5D™ score was 0·65, and the EORTC-QLQ-C30-QL score was 41·1. At 12 months, 13 patients had a clinical response, five were in endoscopic remission, and nine required a colectomy (6 patients) or started new experimental medical therapy (3). IBDQ, EQ-5D™ and EORTC-QLQ-C30-QL scores improved to 167·1 (P < 0·001), 0·80 (P = 0·003) and 61·0 (P < 0·001) respectively. After a median of 3·7 (range 2·3-5·2) years, a further four patients required a colectomy (2) or new experimental medical therapy (2). Thirteen patients had a clinical response and seven were in endoscopic remission. The improvement in IBDQ, EQ-5D™ and the EORTC-QLQ-C30-QL scores remained stable over time. CONCLUSION: Appendicectomy resulted in a clinical response in nearly half of patients with refractory ulcerative colitis and a substantial proportion were in endoscopic remission. Elective appendicectomy should be considered before proctocolectomy in patients with therapy-refractory ulcerative colitis.

ANTECEDENTES: La apendicectomía puede reducir las recaídas y la necesidad de medicación en pacientes con colitis ulcerosa (ulcerative colitis, UC), sin embargo, faltan datos a largo plazo obtenidos de forma prospectiva. El objetivo de este estudio fue analizar el efecto de la apendicectomía en pacientes con UC refractarios al tratamiento. MÉTODOS: En esta serie prospectiva de cohortes multicéntrica, a todos los pacientes consecutivos con UC refractaria remitidos para proctocolectomía entre noviembre de 2012 y junio de 2015 se les recomendó en su lugar someterse a una apendicectomía laparoscópica. El criterio de valoración principal fue la respuesta clínica (disminución de ≥ 3 puntos del sistema de puntuación parcial de Mayo que varía de 0 a 9) a los 12 meses y en el seguimiento a largo plazo. Los criterios de valoración secundarios incluyeron la remisión endoscópica (puntuación endoscópica de Mayo ≤ 1), fracaso (colectomía o inicio de medicación experimental) y cambios en el IBDQ (rango 32-224), EQ-5D y EORTC-QLQ-C30-QL. RESULTADOS: En total, 28 pacientes (13 mujeres, mediana de edad 40,5) se sometieron a una apendicectomía. El IBDQ de referencia promedio fue de 127,0; el EQ-5D 0,65 y el EORTC-QLQ-C30-QL 41,1. A los 12 meses, 13 pacientes presentaban una respuesta clínica, cinco estaban en remisión endoscópica y nueve precisaron colectomía (n = 6) o un nuevo tratamiento médico experimental (n = 3). El IBDQ, EQ-5D y EORTC-QLQ-C30-QL mejoraron a 167,1 (P < 0,001); 0,80 (P = 0,003) y 61,0 (P < 0,001) respectivamente. Después de una mediana de 3,7 años (rango 2,3-5,2), otros cuatro pacientes requirieron una colectomía (n = 2) o un nuevo tratamiento médico experimental (n = 2). Trece pacientes presentaron respuesta clínica y siete se encontraban en remisión endoscópica. La mejora del IBDQ, el EQ-5D y el EORTC-QLQ-C30-QL se mantuvo estable a lo largo del tiempo. CONCLUSIÓN: La apendicectomía consiguió una respuesta clínica en casi la mitad de los pacientes con UC refractaria. La apendicectomía electiva debería ser considerada antes que la proctocolectomía en pacientes con UC refractaria al tratamiento.

Subcutaneous rather than intravenous ustekinumab induction is associated with comparable circulating drug levels and early clinical response: a pilot study.

BACKGROUND: Ustekinumab (USK) is licenced for intravenous induction and subcutaneous (S/C) maintenance in Crohn's disease. AIM: To evaluate ustekinumab trough concentrations and clinical response with exclusive subcutaneous ustekinumab induction. METHODS: Patients with Crohn's disease who initiated treatment with subcutaneous ustekinumab at a single academic centre were included in this pilot study. A dosage of 360 mg ustekinumab was given subcutaneously in divided doses; 180 mg at Week 0, 90 mg at Week 1 and 90 mg at Week 2, with corresponding ustekinumab trough concentrations assessed to Week 8. The primary outcome measures were trough serum ustekinumab levels and clinical remission at Week 8. Secondary outcome measures were trough serum ustekinumab levels at Week 1 & 2 and changes in C-reactive protein, albumin and faecal calprotectin at Week 8. RESULTS: Nineteen patients were included. Median Week 8 ustekinumab trough concentrations were 6.1 µg/mL (Inter-quartile range 4-9.8 µg/mL). There was a significant improvement in Harvey Bradshaw index from Week 0 (median HBI 5; interquartile range 2-8) to Week 8 (median HBI 1; interquartile range 0-3) (P = 0.002). C-reactive protein levels did not change significantly but faecal calprotectin improved significantly; median faecal calprotectin at Week 0 was 533 µg/g; at Week 8, it was 278 µg/g (P = 0.038). CONCLUSIONS: Ustekinumab trough concentrations are comparable whether ustekinumab induction treatment was administered subcutaneously or intravenously. A significant improvement in symptoms and faecal calprotectin was noted. These results support the use of subcutaneous induction as an alternative if there are barriers to intravenous induction.

Long-Term Safety of In Utero Exposure to Anti-TNFα Drugs for the Treatment of Inflammatory Bowel Disease: Results from the Multicenter European TEDDY Study.

OBJECTIVES: The long-term safety of exposure to anti-tumor necrosis factor (anti-TNFα) drugs during pregnancy has received little attention. We aimed to compare the relative risk of severe infections in children of mothers with inflammatory bowel disease (IBD) who were exposed to anti-TNFα drugs in utero with that of children who were not exposed to the drugs. METHODS: Retrospective multicenter cohort study. Exposed cohort: children from mothers with IBD receiving anti-TNFα medication (with or without thiopurines) at any time during pregnancy or during the 3 months before conception. Non-exposed cohort: children from mothers with IBD not treated with anti-TNFα agents or thiopurines at any time during pregnancy or the 3 months before conception. The cumulative incidence of severe infections after birth was estimated using Kaplan-Meier curves, which were compared using the log-rank test. Cox-regression analysis was performed to identify potential predictive factors for severe infections in the offspring. RESULTS: The study population comprised 841 children, of whom 388 (46%) had been exposed to anti-TNFα agents. Median follow-up after delivery was 47 months in the exposed group and 68 months in the non-exposed group. Both univariate and multivariate analysis showed the incidence rate of severe infections to be similar in non-exposed and exposed children (1.6% vs. 2.8% per person-year, hazard ratio 1.2 (95% confidence interval 0.8-1.8)). In the multivariate analysis, preterm delivery was the only variable associated with a higher risk of severe infection (2.5% (1.5-4.3)). CONCLUSIONS: In utero exposure to anti-TNFα drugs does not seem to be associated with increased short-term or long-term risk of severe infections in children.

Approach to the Synthesis of the C1-C11 and C14-C18 portion of Leucascandrolide A.

An asymmetric synthesis of the C1 to C11 and C14 to C18 fragments of the macrocyclic portion of the antibiotic Leucascandrolide A was achieved in 21 total steps from an achiral dienoate. The key 4-hydroxy-2,5-pyran portion of the natural product was established by oxy-Michael cyclization of a 5,7,9,11-tetraol intermediate, which in turn was established by an iterative asymmetric-hydration of dienoates. Alternative strategies for establishing the polyol stereochemistry were explored.

Subclassification of small bowel Crohn's disease using magnetic resonance enterography: a review using evidence-based medicine methodology.

Magnetic resonance enterography (MRE) has a growing role in imaging small bowel Crohn's disease (SBCD), both in diagnosis and assessment of treatment response. Certain SBCD phenotypes respond well to biologic therapy and others require surgery; MRE has an expanding role in triaging these patients. In this review, we evaluate the MRE signs that subclassify SBCD using evidence-based medicine (EBM) methodology and provide a structured approach to MRE interpretation.

Altered expression of caspases-4 and -5 during inflammatory bowel disease and colorectal cancer: Diagnostic and therapeutic potential.

Caspases are a group of proteolytic enzymes involved in the co-ordination of cellular processes, including cellular homeostasis, inflammation and apoptosis. Altered activity of caspases, particularly caspase-1, has been implicated in the development of intestinal diseases, such as inflammatory bowel disease (IBD) and colorectal cancer (CRC). However, the involvement of two related inflammatory caspase members, caspases-4 and -5, during intestinal homeostasis and disease has not yet been established. This study demonstrates that caspases-4 and -5 are involved in IBD-associated intestinal inflammation. Furthermore, we found a clear correlation between stromal caspase-4 and -5 expression levels, inflammation and disease activity in ulcerative colitis patients. Deregulated intestinal inflammation in IBD patients is associated with an increased risk of developing CRC. We found robust expression of caspases-4 and -5 within intestinal epithelial cells, exclusively within neoplastic tissue, of colorectal tumours. An examination of adjacent normal, inflamed and tumour tissue from patients with colitis-associated CRC confirmed that stromal expression of caspases-4 and -5 is increased in inflamed and dysplastic tissue, while epithelial expression is restricted to neoplastic tissue. In addition to identifying caspases-4 and -5 as potential targets for limiting intestinal inflammation, this study has identified epithelial-expressed caspases-4 and -5 as biomarkers with diagnostic and therapeutic potential in CRC.