0000000000087982
AUTHOR
Joaquín Hinojosa
Physician Perspectives on Unresolved Issues in the Management of Ulcerative Colitis: The UC Horizons Project.
BACKGROUND There is still uncertainty about what constitutes the best therapeutic practice in ulcerative colitis (UC). OBJECTIVE The purpose of the "UC Horizons Project" was to raise a series of questions regarding the management of UC to provide responses based on the best scientific evidence available. METHODS The 11 members of the scientific committee prepared draft answers to the 10 questions from available evidence after a literature search. A total of 48 Spanish gastroenterology specialists nationwide participated in the project. The national meeting discussed the 10 issues in working groups and reached consensus regarding the recommendations by anonymous, interactive vote following t…
Succinate receptor mediates intestinal inflammation and fibrosis.
Succinate, an intermediate of the tricarboxylic acid cycle, is accumulated in inflamed areas and its signaling through succinate receptor (SUCNR1) regulates immune function. We analyze SUCNR1 expression in the intestine of Crohn's disease patients and its role in murine intestinal inflammation and fibrosis. We show that both serum and intestinal succinate levels and SUCNR1 expression in intestinal surgical resections were higher in CD patients than in controls. SUCNR1 co-localized with CD86, CD206, and alpha-SMA(+) cells in human intestine and we found a positive and significant correlation between SUCNR1 and alpha-SMA expression. In human isolated fibroblasts from CD patients SUCNR1 expres…
Effectiveness and Safety of Ustekinumab in Ulcerative Colitis: Real-world Evidence from the ENEIDA Registry
Abstract Background and Aims The development programm UNIFI has shown promising results of ustekinumab in ulcerative colitis [UC] treatment which should be confirmed in clinical practice. We aimed to evaluate the durability, effectiveness, and safety of ustekinumab in UC in real life. Methods Patients included in the prospectively maintained ENEIDA registry, who received at least one intravenous dose of ustekinumab due to active UC [Partial Mayo Score [PMS]>2], were included. Clinical activity and effectiveness were defined based on PMS. Short-term response was assessed at Week 16. Results A total of 95 patients were included. At Week 16, 53% of patients had response [including 35% o…
Induction of CD36 and thrombospondin-1 in macrophages by hypoxia-inducible factor 1 and its relevance in the inflammatory process.
Inflammation is part of a complex biological response of vascular tissue to pathogens or damaged cells. First inflammatory cells attempt to remove the injurious stimuli and this is followed by a healing process mediated principally by phagocytosis of senescent cells. Hypoxia and p38-MAPK are associated with inflammation, and hypoxia inducible factor 1 (HIF-1) has been detected in inflamed tissues. We aimed to analyse the role of p38-MAPK and HIF-1 in the transcriptional regulation of CD36, a class B scavenger receptor, and its ligand thrombospondin (TSP-1) in macrophages and to evaluate the involvement of this pathway in phagocytosis of apoptotic neutrophils. We have also assessed HIF-1α, p…
Diminished Vitamin D Receptor Protein Levels in Crohn´s Disease Fibroblasts: Effects of Vitamin D
Vitamin D (VD) deficiency has been associated to Crohn´
Adalimumab vs Azathioprine in the Prevention of Postoperative Crohn's Disease Recurrence. A GETECCU Randomised Trial.
Background and aims Postoperative recurrence of Crohn's disease [POR-CD] is almost certain if no prophylaxis is administered. Evidence for optimal treatment is lacking. Our aim was to compare the efficacy of adalimumab [ADA] and azathioprine [AZA] in this setting. Methods We performed a phase 3, 52-week, multicentre, randomised, superiority study [APPRECIA], in which patients with ileocolonic resection were randomised either to ADA 160-80-40 mg subcutaneously [SC] or AZA 2.5 mg/kg/day, both associated with metronidazole. The primary endpoint was endoscopic recurrence at 1 year [Rutgeerts i2b, i3, i4], as evaluated by a blinded central reader. Results We recruited 91 patients [median age 35.…
Information resources used by patients with inflammatory bowel disease: Satisfaction, expectations and information gaps.
Abstract Background and purpose Information received by IBD patients about their disease is of particular importance. The objective of the study was to determine the information resources these patients used, together with their perceived information gaps and expected preferences. Patients and methods A prospective, observational, cross-sectional study conducted on IBD patients attending 13 Spanish hospitals during 2008. Patients completed a semi-structured 52-question survey. Results Survey was adequately completed by 379 of 385 patients (98%), of whom 57% had Crohn's disease and 43% ulcerative colitis. Mean patient age was 37.9 years (range, 16–76 years). Gastroenterologists were the most…
Quality of life during one year of postoperative prophylactic drug therapy after intestinal resection in Crohn's patients: Results of the APPRECIA trial
Background: In APPRECIA trial, Crohn's disease (CD) patients undergoing intestinal resection were randomized to postoperative adalimumab (ADA) or azathioprine (AZA). Aims: To evaluate health-related quality of life (HRQoL) in APPRECIA trial. Methods: HRQoL was evaluated using disease-specific shortened Spanish version of the IBDQ (SIBDQ-9) and generic European Quality of Life-5 Dimensions (EQ-5D) questionnaires, completed at baseline and at weeks 24 and 52. Results: Sixty-one patients (37 ADA and 24 AZA) had evaluable data for HRQoL. Patients treated with ADA or AZA had significant improvement from baseline to weeks 24 and 52 in SIBDQ-9 and EQ-5D (p < 0.001 and p = 0.006 for all comparisons…
M1 Macrophages Activate Notch Signalling in Epithelial Cells: Relevance in Crohn's Disease
Background: The Notch signalling pathway plays an essential role in mucosal regeneration, which constitutes a key goal of Crohn's disease (CD) treatment. Macrophages coordinate tissue repair and several phenotypes have been reported which differ in the expression of surface proteins, cytokines and hypoxia-inducible factors (HIFs). We analysed the role of HIFs in the expression of Notch ligands in macrophages and the relevance of this pathway in mucosal regeneration. Methods: Human monocytes and U937-derived macrophages were polarized towards the M1 and M2 phenotypes and the expression levels of HIF-1α, HIF-2α, Jagged 1 (Jag1) and delta-like 4 (Dll4) were evaluated. The effects of macrophage…
Hypoxic macrophages impair autophagy in epithelial cells through Wnt1: relevance in IBD.
A defective induction of epithelial autophagy may have a role in the pathogenesis of inflammatory bowel diseases. This process is regulated mainly by extracellular factors such as nutrients and growth factors and is highly induced by diverse situations of stress. We hypothesized that epithelial autophagy is regulated by the immune response that in turn is modulated by local hypoxia and inflammatory signals present in the inflamed mucosa. Our results reveal that HIF-1 alpha and Wnt1 were co-localized with CD68 in cells of the mucosa of IBD patients. We have observed increased protein levels of beta-catenin, phosphorylated mTOR, and p62 and decreased expression of LC3II in colonic epithelial …
A Single Nucleotide Polymorphism in the Vitamin D Receptor Gene Is Associated With Decreased Levels of the Protein and a Penetrating Pattern in Crohn’s Disease
Background: Vitamin D signaling modulates inflammation through the vitamin D receptor (VDR). The synonymous single nucleotide polymorphism (SNP) rs731236, located in the VDR gene, has been associated with a higher risk of Crohn's disease (CD). We analyzed differences in VDR expression levels among CD patients who were homozygous for allelic variants in this SNP and their relevance for disease course. Methods: DNA was extracted from blood samples of CD patients, and SNP genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism. Fresh blood from patients was used to isolate peripheral blood mononuclear cells (PBMCs) or to determine the expression of adhesi…
P028 The Apa I polymorphism in the Vitamin D receptor gene is associated with a stricturing behaviour in Crohn′s disease patients
Abstract Background Vitamin D receptor (VDR) is a member of the nuclear receptor family of transcription factors that plays an immunomodulatory role in the gastrointestinal tract through binding Vitamin D. Single-nucleotide polymorphisms (SNPs) in the VDR gene have been related to inflammatory bowel disease. Indeed, Crohn′s disease (CD) patients carrying the Taq I polymorphism in VDR gene run a higher risk of developing a penetrating behaviour. We analyse here the association between the VDR SNPs Taq I, Bsm I, Apa I and Fok I and the clinical characteristics of CD. Methods DNA was extracted from blood samples from 80 patients diagnosed with CD from the Hospital of Manises (Valencia). Four p…
Prospective study of morphologic and functional changes with time in the mucosa of the ileoanal pouch: functional appraisal using transmucosal potential differences.
PURPOSE: This study was undertaken to investigate the morphologic and functional changes with time in the mucosa of the ileoanal pouch. METHODS: A morphologic study by histopathologic analysis, mucosal morphometry, and mucin histochemistry and a functional study by analysis of transmucosal potential difference were performed in 27 patients with an ileoanal J-pouch after restorative proctocolectomy for ulcerative colitis. In 19 patients with a normal ileoanal pouch, two prospective follow-up analyses were performed after median functional pouch times of 14 and 39 months. We also evaluated eight patients with the diagnosis of pouchitis (median follow-up, 52.5 months). RESULTS: In the normal i…
M2 Macrophages Activate WNT Signaling Pathway in Epithelial Cells: Relevance in Ulcerative Colitis
Macrophages, which exhibit great plasticity, are important components of the inflamed tissue and constitute an essential element of regenerative responses. Epithelial Wnt signalling is involved in mechanisms of proliferation and differentiation and expression of Wnt ligands by macrophages has been reported. We aim to determine whether the macrophage phenotype determines the expression of Wnt ligands, the influence of the macrophage phenotype in epithelial activation of Wnt signalling and the relevance of this pathway in ulcerative colitis. Human monocyte-derived macrophages and U937-derived macrophages were polarized towards M1 or M2 phenotypes and the expression of Wnt1 and Wnt3a was analy…