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Ward JB, Lajczak NK, Kelly OB, O'Dwyer AM, Giddam AK, Ní Gabhann J, Franco P, Tambuwala MM, Jefferies CA, Keely S, Roda A, Keely SJ. Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon. Am J Physiol Gastrointest Liver Physiol 312: G550-G558, 2017. First published March 30, 2017; doi:10.1152/ajpgi.00256.2016.-Inflammatory bowel diseases (IBD) comprise a group of common and debilitating chronic intestinal disorders for which currently available therapies are often unsatisfactory. The naturally occurring secondary bile acid, ursodeoxycholic acid (UDCA), has well-established anti-inflammatory and cytoprotective actions and may therefore be effective in treating IBD. We aimed to investigate regulation of colonic inflammatory responses by UDCA and to determine the potential impact of bacterial metabolism on its therapeutic actions. The anti-inflammatory efficacy of UDCA, a nonmetabolizable analog, 6α-methyl-UDCA (6-MUDCA), and its primary colonic metabolite lithocholic acid (LCA) was assessed in the murine dextran sodium sulfate (DSS) model of mucosal injury. The effects of bile acids on cytokine (TNF-α, IL-6, Il-1ß, and IFN-γ) release from cultured colonic epithelial cells and mouse colonic tissue in vivo were investigated. Luminal bile acids were measured by gas chromatography-mass spectrometry. UDCA attenuated release of proinflammatory cytokines from colonic epithelial cells in vitro and was protective against the development of colonic inflammation in vivo. In contrast, although 6-MUDCA mimicked the effects of UDCA on epithelial cytokine release in vitro, it was ineffective in preventing inflammation in the DSS model. In UDCA-treated mice, LCA became the most common colonic bile acid. Finally, LCA treatment more potently inhibited epithelial cytokine release and protected against DSS-induced mucosal inflammation than did UDCA. These studies identify a new role for the primary metabolite of UDCA, LCA, in preventing colonic inflammation and suggest that microbial metabolism of UDCA is necessary for the full expression of its protective actions.NEW & NOTEWORTHY On the basis of its cytoprotective and anti-inflammatory actions, the secondary bile acid ursodeoxycholic acid (UDCA) has well-established uses in both traditional and Western medicine. We identify a new role for the primary metabolite of UDCA, lithocholic acid, as a potent inhibitor of intestinal inflammatory responses, and we present data to suggest that microbial metabolism of UDCA is necessary for the full expression of its protective effects against colonic inflammation.
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Antiinflamatorios/farmacología , Colitis/prevención & control , Colon/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Ácido Litocólico/farmacología , Ácido Ursodesoxicólico/farmacología , Animales , Bacterias/metabolismo , Biotransformación , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/microbiología , Colon/metabolismo , Colon/microbiología , Colon/patología , Citocinas/metabolismo , Sulfato de Dextran , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Microbioma Gastrointestinal , Células HT29 , Humanos , Mediadores de Inflamación/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Masculino , Ratones Endogámicos C57BL , Factores de Tiempo , Ácido Ursodesoxicólico/análogos & derivados , Ácido Ursodesoxicólico/metabolismoRESUMEN
UNLABELLED: Proton pump inhibitors (PPIs) are used to treat upper gastrointestinal tract disorders. Their efficacy and perceived safety have led to widespread prescription. This is not without effect, in terms of adverse events and resource utilization. AIM: To prospectively assess oral PPI prescription in hospitalized patients. METHODS: PPI prescription in consecutive hospitalized patients was assessed. Indication and dose were assessed by patient interview and medical record review. Comparisons with current published prescribing guidelines were made. RESULTS: Four hundred and forty-seven patients were included. 57.5 % were prescribed PPIs. 26.8 % prescriptions were for inappropriate or unclear indications. 68.4 % were on higher doses than guidelines recommended, of which 41.6 % could have undergone dose reduction, and 26.5 % discontinued. In a multivariate analysis, age, gender, and length of stay had no association with PPI prescription. Although aspirin use was appropriately associated with PPI prescription (RR: 1.8, 95 % CI 1.127-3.69; p < 0.05), the PPI was often given at higher than recommended doses (p < 0.001). This may reflect older age and multiple risk factors in this subset. Surgical patients commenced more PPIs and at higher dosages (p < 0.001). Omeprazole and lansoprazole were most often inappropriately prescribed (p < 0.01, p < 0.001, respectively). CONCLUSION: Inappropriate PPI therapy is still a problem in hospitals, though it appears to be at a lower level compared with previous studies. Awareness of evidence-based guidelines and targeted medicine reconciliation strategies are essential for cost-effective and safe use of these medications.
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Prescripción Inadecuada/estadística & datos numéricos , Inhibidores de la Bomba de Protones/uso terapéutico , Administración Oral , Anciano , Estudios Transversales , Dispepsia/tratamiento farmacológico , Dispepsia/etiología , Femenino , Reflujo Gastroesofágico/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Guías de Práctica Clínica como Asunto , Estudios Prospectivos , Inhibidores de la Bomba de Protones/administración & dosificaciónRESUMEN
Dihydroxy bile acids, such as chenodeoxycholic acid (CDCA), are well known to promote colonic fluid and electrolyte secretion, thereby causing diarrhoea associated with bile acid malabsorption. However, CDCA is rapidly metabolised by colonic bacteria to ursodeoxycholic acid (UDCA), the effects of which on epithelial transport are poorly characterised. Here, we investigated the role of UDCA in the regulation of colonic epithelial secretion. Cl(-) secretion was measured across voltage-clamped monolayers of T84 cells and muscle-stripped sections of mouse or human colon. Cell surface biotinylation was used to assess abundance/surface expression of transport proteins. Acute (15 min) treatment of T84 cells with bilateral UDCA attenuated Cl(-) secretory responses to the Ca(2+) and cAMP-dependent secretagogues carbachol (CCh) and forskolin (FSK) to 14.0 ± 3.8 and 40.2 ± 7.4% of controls, respectively (n = 18, P < 0.001). Investigation of the molecular targets involved revealed that UDCA acts by inhibiting Na(+)/K(+)-ATPase activity and basolateral K(+) channel currents, without altering their cell surface expression. In contrast, intraperitoneal administration of UDCA (25 mg kg(-1)) to mice enhanced agonist-induced colonic secretory responses, an effect we hypothesised to be due to bacterial metabolism of UDCA to lithocholic acid (LCA). Accordingly, LCA (50-200 µm) enhanced agonist-induced secretory responses in vitro and a metabolically stable UDCA analogue, 6α-methyl-UDCA, exerted anti-secretory actions in vitro and in vivo. In conclusion, UDCA exerts direct anti-secretory actions on colonic epithelial cells and metabolically stable derivatives of the bile acid may offer a new approach for treating intestinal diseases associated with diarrhoea.
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Antidiarreicos/farmacología , Colon/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Ácido Ursodesoxicólico/farmacología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Ácidos y Sales Biliares/metabolismo , Colon/citología , Colon/fisiología , Células Epiteliales/fisiología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Bloqueadores de los Canales de Potasio/farmacología , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidoresRESUMEN
BACKGROUND: MicroRNAs [miRNAs] are key modulators of gene expression in Crohn's disease [CD] and may drive tissue-specific molecular alterations underlying CD susceptibility. In this study, we analysed differential miRNA expression between CD and healthy subjects across ileal and colonic tissues. METHODS: A cohort of CD and healthy control [HC] subjects was recruited and clinical data collected. Endoscopically quiescent CD [CDq] was defined as inactive or mild by the Simple Endoscopic Score for CD. Total RNA was extracted from endoscopic biopsies taken from the terminal ileum and sigmoid colon. miRNA expression was quantified using NanoString Technologies. Statistical significance was assessed across biopsy site and diagnosis per miRNA, and corrected for multiple testing. RESULTS: In total, 23 CDq and 38 HC subjects were enrolled; 112 samples were included in the analysis, 51 from the ileum and 61 from the colon. We found 47 miRNAs differentially expressed by biopsy site in healthy tissue. Nine miRNAs were differentially expressed across HC and CDq, accounting for biopsy location. One of these, miR-223-3p, showed age and sex effects. We identified miRNA expression driven by diagnosis targeting genes involved in chemokine and cytokine signalling. miR-31-5p expression was driven by location and may be a biomarker for location subtypes in CD. CONCLUSIONS: We identified differentially expressed miRNAs in healthy ileal and colonic tissues. We discovered spatial miRNA expression patterns in CD and HC, suggesting site-specific regulation in subjects with no or minimal intestinal inflammation. These miRNAs target genes involved in immunoregulatory processes, suggesting a functional, tissue-specific role in CD.
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Colon/metabolismo , Enfermedad de Crohn/metabolismo , Íleon/metabolismo , MicroARNs/metabolismo , Adulto , Biopsia , Estudios de Casos y Controles , Colon/patología , Femenino , Humanos , Íleon/patología , Masculino , Persona de Mediana Edad , Regulación hacia ArribaRESUMEN
BACKGROUND: Sacroiliitis, an inflammatory arthropathy associated with ankylosing spondylitis (AS), is found in patients with inflammatory bowel disease (IBD) but may go undiagnosed. The aims of this study were to assess prevalence of sacroiliitis in IBD and to determine association between clinical characteristics of IBD and sacroiliitis. METHODS: Inflammatory bowel disease patients undergoing abdomino-pelvic computed tomography (CT) for any indication (2006-2015) were identified. Using standardized CT scoring, sacroiliitis was confirmed. Two blinded readers used a standardised model where presence of ankylosis or erosion score >3 indicated sacroiliitis. Inflammatory bowel disease scoring was blinded to the presence of sacroiliitis. Demographics, IBD characteristics, clinical activity (Harvey Bradshaw Index >4, Mayo >2, as denoted by attending physician), endoscopic activity (Simple Endoscopic Score for Crohn's Disease >4/Mayo subscore >1), and arthritis/extraintestinal manifestations (EIMS) were recorded. Comparisons were made between those with/without sacroiliitis. RESULTS: Three hundred sixteen patients were included (50% male; 74% Crohn's disease [CD]). Computed tomography scoring identified 49 (16%) with sacroiliitis. Radiologists had reported sacroiliitis in 33% of these. Five patients had been to a spondylitis clinic. Thirty-three of 49 had abdominal x-rays; 64% of these fulfilled the imaging component of Modified New York criteria for AS. More than 5 sacroiliac erosions were associated with radiologist-reported sacroiliitis (P < 0.0001). There was no difference in prevalence between CD and ulcerative colitis. Sacroiliitis was associated with male sex (63.3% vs 47.9%; odds ratio [OR], 1.8; P = 0.04), known arthritis (41% vs 12%; OR, 4.7; P < 0.0001), pain as an IBD symptom (77.7% vs 56.9%; P = 0.03), and CD inflammatory phenotype (P = 0.01). Endoscopic activity, location, and extent were not associated. CONCLUSIONS: Sacroiliitis is underdiagnosed in IBD and is associated with male sex, arthritis, and inflammatory CD. Data support targeted screening in at-risk patients.
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Artritis/epidemiología , Enfermedades Inflamatorias del Intestino/fisiopatología , Sacroileítis/epidemiología , Espondilitis Anquilosante/epidemiología , Adulto , Artritis/diagnóstico por imagen , Artritis/patología , Canadá/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Prevalencia , Pronóstico , Sacroileítis/diagnóstico por imagen , Sacroileítis/patología , Espondilitis Anquilosante/diagnóstico por imagen , Espondilitis Anquilosante/patología , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
BACKGROUND AND AIMS: MicroRNAs [miRNAs] have emerged as important regulators in inflammatory bowel disease [IBD]. This study investigated differential expression of miRNAs across clinical phenotypes in a well-characterized cohort of IBD patients and healthy controls [HCs]. METHODS: A cohort of Crohn's disease [CD] and ulcerative colitis [UC] patients and HCs was prospectively accrued. Total RNA was extracted from peripheral blood mononuclear cells for all subjects. miRNA expression was measured using NanoString technologies. The subjects were stratified according to disease activity and location. Statistical significance was assessed per miRNA across outcomes and corrected for multiple testing. miRNA regulation of transcription of important results was confirmed in vitro by a dual luciferase reporter assay and autophagy function was evaluated using immunofluorescence imaging of LC3 puncta in HeLa cells. RESULTS: In total, 120 subjects were enrolled. Seventy-four miRNAs were differentially expressed across CD, UC and HCs. Comparing quiescent CD [CDq] with HCs we found ten miRNAs upregulated in CDq. When comparing colonic CD [CCD] to UC, seven miRNAs were upregulated in CCD. The most differentially expressed miRNA in CCD vs UC was miR-874-3p, and we showed its possible utility as a biomarker of differential diagnosis. We showed miR-874-3p targets ATG16L1 and reduces its expression in vitro. An miR-874-3p mimic dysregulates autophagy by a reduction of LC3 in vitro. CONCLUSIONS: We identified unique miRNA signatures expressed in distinct IBD phenotypes. These associations highlight pathways dysregulated by aberrant miRNA expression, revealing possible mechanisms underlying the pathophysiology of IBD, but also suggest a cluster of miRNAs as readily accessible biomarkers to aid in differential diagnosis.
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Colitis Ulcerosa/sangre , Colitis Ulcerosa/diagnóstico , Enfermedad de Crohn/sangre , Enfermedad de Crohn/diagnóstico , MicroARNs/sangre , MicroARNs/genética , Factor de Crecimiento Transformador beta/sangre , Adulto , Anciano , Autofagia/genética , Proteínas Relacionadas con la Autofagia/genética , Biomarcadores/sangre , Estudios de Casos y Controles , Colitis Ulcerosa/genética , Colon , Enfermedad de Crohn/genética , Diagnóstico Diferencial , Femenino , Células HeLa , Humanos , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Transducción de Señal , Proteína smad3/metabolismo , Regulación hacia Arriba , Adulto JovenRESUMEN
BACKGROUND: The utility of fecal calprotectin (FC) in small intestinal Crohn's disease (CD) is unclear. We examined how reliably FC reflects clinical and mucosal disease activity in small intestinal CD, colonic CD, and ulcerative colitis (UC). METHODS: A total of 72 Inflammatory Bowel Disease (IBD) patients (23 colonic CD, 14 isolated small intestinal CD, and 35 UC) were included. Clinical activity was assessed using the Harvey-Bradshaw Index (HBI) (CD) and Mayo score (UC). Inflammatory activity was assessed through ileocolonoscopy, cross-sectional imaging, C-reactive protein (CRP), and FC. Clinical activity was defined as HBI > 4 or Mayo clinical score ≥ 3. Endoscopy activity was defined as Mayo endoscopic subscore ≥ 1, SES-CD score ≥ 3, and Rutgeerts > i1. RESULTS: In UC, FC was correlated with the Mayo clinical score (P < 0.0001) and was highly correlated with the total Mayo score (P < 0.0001). A cut-off value of FC 100 µg/g provided sensitivity of 88% and specificity 100% for endoscopic activity. FC was lower for patients with endoscopic and clinical remission compared to active endoscopic disease (median 100 vs 1180 µg/g, P < 0.0001). In colonic CD, there was a significant correlation between FC and endoscopic activity (P < 0.001). For an FC cut-off value of 100 µg/g, sensitivity was 100%, and specificity was 67%. In contrast, for isolated small intestinal CD, there was no significant correlation between FC and objective disease activity measured by either endoscopy or imaging (AUC 0.52, P = 0.58). CONCLUSION: FC is reliable for the detection of colonic mucosal inflammation in both UC and CD but is less sensitive and reliable in the detection of small intestinal CD.
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BACKGROUND: Adequate infliximab (IFX) levels are associated with favorable outcomes in inflammatory bowel disease. Using therapeutic drug monitoring (TDM) to guide dosing is cost effective and associated with clinical improvement, but effect on endoscopic outcomes remains unclear. METHODS: Primary responders to IFX who underwent dose escalation (2008-2014) were reviewed. Patients with active endoscopic disease were included. Two cohorts were examined: TDM-based decision to escalate (TDM) and clinical decision (non-TDM). Outcomes recorded at median 6 months after adjustment included endoscopic remission (Mayo <1, Simple Endoscopic Score for Crohn's Disease <3), C-reactive protein, and inflammatory bowel disease-specific health care utilization. Postadjustment IFX and antibodies to infliximab levels discriminant for endoscopic remission were determined. Multivariable regression evaluated independent predictors of remission. RESULTS: Of note, 312 dose optimizations were examined (149 TDM and 163 non-TDM). Clinically, groups were similar. Sixty-three percent TDM attained postadjustment endoscopic remission compared with 48% non-TDM (P < 0.05). Sixty-nine percentage TDM had significant clinical response (57% non-TDM [P < 0.01]); fewer were hospitalized (22% TDM versus 35% non-TDM, P = 0.025). Patients with ulcerative colitis had shorter time to escalation (10 versus 20 mo, P < 0.0001). Median IFX levels increased after escalation in TDM (1.5 [pre] and 11 µg/mL [post]; P < 0.0001) and were higher than non-TDM postadjustment levels (11 versus 6.5 µg/mL, P = 0.015). Postadjustment IFX >4.5 µg/mL (area under curve = 0.8; 95% confidence interval, 0.71-0.88) and antibodies to infliximab <3.3 U/mL (area under curve = 0.70; 95% confidence interval, 0.63-0.81) were associated with endoscopic remission. Multivariable analysis showed that IFX concentration (odds ratio 1.2 [95% confidence interval, 1.1-1.3]; P < 0.0001) remained an independent predictor of endoscopic remission. CONCLUSIONS: TDM before dose adjustment is associated with higher postadjustment levels and endoscopic remission.
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Toma de Decisiones Clínicas , Monitoreo de Drogas , Endoscopía/métodos , Fármacos Gastrointestinales/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Infliximab/uso terapéutico , Adolescente , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Enfermedades Inflamatorias del Intestino/patología , Masculino , Persona de Mediana Edad , Pronóstico , Inducción de Remisión , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: There is a need for better, less-invasive disease activity indices that provide a representative assessment of endoscopic disease activity. We developed a new clinical score that incorporates the Harvey-Bradshaw index [HBI] with modified patient-reported outcomes [PROp] and physician [clinician]-reported outcomes [PROc] and assessed its ability to measure endosopic disease activity in ileocolonic Crohn's disease [CD]. METHODS: A cohort of 88 CD patients undergoing colonoscopy was accrued in a prospective fashion. In total, 48 of the subjects were CD cases and 40 had already undergone a post-operative ileocolonic resection [post-op CD]. Each patient underwent multiple, endoscopist-blinded assessments including: HBI score, a PROp question asking for patient perception of disease activity status, a PROc question for clinician perception of disease activity status and C-reactive protein [CRP]. Active endoscopic disease was defined as Simple Endoscopic Score for CD [SES-CD] ≥ 3 for CD subjects and Rutgeerts score > i1 for post-op CD subjects. RESULTS: Clinical remission as defined by the HBI did not accurately reflect endoscopic remission as defined by the SES-CD (area under the curve [AUC] = 0.54). Combining the HBI with PROp and PROc scores and then further adding CRP significantly improved the correlation with SES-CD [AUC = 0.78 and AUC = 0.88, respectively, p < 0.00001]. In post-op CD, HBI-defined remission also performed poorly against endoscopic remission defined by the Rutgeerts score [AUC = 0.52]. Combining HBI with PROp and the PROc scores and then further adding CRP did not significantly improve the model [AUC = 0.65 and AUC = 0.61, respectively, p = NS]. CONCLUSION: In CD, the HBI correlates poorly with endoscopic disease activity. However, the HBI-PRO score, which incorporated PROp, PROc, CRP and HBI, significantly improved its ability to predict endoscopic activity in ileocolonic CD without prior surgery.
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Colonoscopía , Enfermedad de Crohn/patología , Índice de Severidad de la Enfermedad , Adulto , Colon/patología , Colon/cirugía , Colonoscopía/métodos , Enfermedad de Crohn/cirugía , Femenino , Humanos , Masculino , Inducción de Remisión , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Data regarding the correlation of histologic and endoscopic healing with fecal calprotectin (FC) are conflicting. We examined how FC levels correlate with histological and endoscopic remission in colonic inflammatory bowel disease. METHODS: Fifty-eight patients (23 with colonic Crohn's disease [CD] and 35 with ulcerative colitis [UC]) were included. Clinical activity was assessed by Harvey-Bradshaw index (CD) and Mayo score (UC). Inflammatory activity was assessed by ileocolonoscopy, C-reactive protein, and FC. Clinical remission was defined as Harvey-Bradshaw index ≤ 4 or Mayo score ≤ 2 and mucosal healing as Mayo endoscopic subscore = 0 (UC), and Simple Endoscopic Score-CD <3 (CD). Histologic activity was assessed in 27 patients (15 CD, 12 UC). Histological remission was defined as absence of active inflammation (Geboes score <3.1) and absence of basal plasmacytosis. RESULTS: In UC, FC correlated with clinical Mayo score (r = 0.63, P < 0.0001). This correlation was strengthened by adding the endoscopic subscore (r = 0.90, P < 0.0001). The endoscopic subscore also independently correlated with FC (r = 0.96, P < 0.0001). In Crohn's colitis, endoscopic activity correlated with FC (r = 0.61, P < 0.001). FC levels were lower overall for patients with endoscopic remission compared with active endoscopic disease (median 100 versus 1180 µg/g, P < 0.0001). FC also correlated with histological remission (Geboes score < 3.1) and absence of basal plasmacytosis in CD (r = 0.77, r = 0.80, respectively; P < 0.01). Area under the curve for FC as a predictor of histological remission (Geboes score <3.1) was 0.95 (95% CI, 0.82-1). CONCLUSIONS: Low FC correlates well with histological remission and mucosal healing in colonic inflammatory bowel disease and is thus a clinically useful surrogate for inflammatory activity.
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Biomarcadores/metabolismo , Colitis Ulcerosa/patología , Enfermedad de Crohn/patología , Heces/química , Inflamación/patología , Complejo de Antígeno L1 de Leucocito/metabolismo , Membrana Mucosa/patología , Adolescente , Adulto , Anciano , Proteína C-Reactiva/metabolismo , Estudios de Cohortes , Colitis Ulcerosa/metabolismo , Enfermedad de Crohn/metabolismo , Endoscopía , Ensayo de Inmunoadsorción Enzimática , Femenino , Estudios de Seguimiento , Histocitoquímica , Humanos , Inflamación/metabolismo , Masculino , Persona de Mediana Edad , Membrana Mucosa/metabolismo , Pronóstico , Curva ROC , Inducción de Remisión , Índice de Severidad de la Enfermedad , Cicatrización de Heridas , Adulto JovenRESUMEN
BACKGROUND: Inflammatory pouch complications refractory to first-line therapies remain problematic following ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC). We evaluated infliximab efficacy and associations with therapeutic response. METHODS: Data from individuals who underwent colectomy and IPAA for UC (2000-2014) were reviewed. Patients with chronic refractory pouchitis (CP) and Crohn's disease (CD)-like outcomes treated with infliximab were included. Pre-treatment parameters and response at median 8 (initial) and 48 weeks (sustained) were measured. Complete response was defined as symptomatic and endoscopic resolution with modified Pouchitis Disease Activity Index (mPDAI) <5. Partial response included mPDAI improvement >2. Serum was analysed for Anti-Saccharomyces cerevisiae antibodies (ASCA), anti-OmpC, anti-CBir1 and perinuclear Anti-Neutrophil Cytoplasmic Antibodies (pANCA). RESULTS: One hundred and fifty-two patients with CP or a CD-like phenotype were identified. Forty-two were treated with infliximab (33% male; age 32.6±2.6 years, 28.5% CD-like). Post-induction response was achieved in 74% (48% complete) and sustained response in 62.6% (29.6% complete). Mean mPDAI and C-reactive protein declined from 8.5±0.3 to 2±3.4 (p < 0.002) and from 29.48±6.2 to 5.76±1.6mg/L (p < 0.001), respectively. Female gender, smoking and presence of anti-CBir1 were associated with infliximab use (p < 0.01) but not response. Pre-treatment mPDAI <10 (p < 0.01), resolution of rectal bleeding (p < 0.001 ) and week 8 endoscopic activity were associated with sustained response (p = 0.04; odds ratio [OR] 2.2; 95% confidence interval [CI] 1.1-16.5]). More than 2 positive antimicrobial antibody titres were associated with non-response (p < 0.05), but did not retain significance in multivariate analysis (p = 0.197; OR 0.632; 95% CI 0.31-1.2). CONCLUSIONS: Infliximab can effectively treat inflammatory pouch complications. Pre-treatment mPDAI <10 and early endoscopy may identify responders.
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Colitis Ulcerosa/tratamiento farmacológico , Reservorios Cólicos/efectos adversos , Fármacos Gastrointestinales/uso terapéutico , Infliximab/uso terapéutico , Reservoritis/tratamiento farmacológico , Adulto , Colitis Ulcerosa/cirugía , Femenino , Humanos , Masculino , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Eosinophilic oesophagitis is a clinicopathological disease characterized by oesophageal eosinophilia and gastrointestinal symptoms. Currently, the optimal treatment regimens remain unclear. The pathogenesis of eosinophilic oesophagitis appears to involve immune dysregulation, while acid reflux may have a secondary role; the mainstays in treatment are aimed principally at these dual processes. While a trial of a PPI is worthwhile it is likely that PPI therapy is treating concurrent acid reflux rather than true eosinophilic oesophagitis. Dietary elimination with elemental feed is safe but poorly tolerated. Swallowed topical steroids are the mainstay of commercially available therapies. Both fluticasone and budesonide have been proven to be beneficial both symptomatically and in reducing oesophageal eosinophil counts in the short and medium term. Basic studies have determined a role for IL-5 in oesophageal remodelling in eosinophilic esophagitis. Initial clinical studies have shown single or multiple infusions of monoclonal antibody to IL-5 to be well tolerated and to cause a long-term decrease in both peripheral and sputum eosinophil count in these eosinophil driven conditions. At present, swallowed corticosteroids are the mainstay of treatment for patients with eosinophilic oesophagitis in patients failing PPI therapy. Studies have been heterogenous in their diagnostic criteria for eosinophilic oesophagitis and in the definition of response to therapy, making comparison of results difficult.
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Esofagitis Eosinofílica/tratamiento farmacológico , Corticoesteroides/uso terapéutico , Androstadienos/uso terapéutico , Budesonida/uso terapéutico , Dietoterapia , Esofagitis Eosinofílica/dietoterapia , Esofagitis Eosinofílica/inmunología , Esofagitis Eosinofílica/fisiopatología , Fluticasona , Humanos , Inhibidores de la Bomba de Protones/uso terapéuticoRESUMEN
INTRODUCTION: Eosinophilic oesophagitis is a recently recognized oesophageal disorder characterized by a combination of clinical and endoscopic features as well as the histological finding on oesophageal biopsy of greater than 15 eosinophils per high powered field. Recent reports suggest eosinophilic oesophagitis is increasing in incidence and this increase cannot be fully explained by increased recognition of the disorder. The aim of this retrospective study was to assess the incidence of eosinophilic oesophagitis within the catchment area of a tertiary referral hospital in southwest Dublin, Ireland. METHODS: The histopathology database at the Adelaide and Meath Hospital was used to identify all oesophageal biopsies obtained between January 2000 and July 2008 reported to show evidence of oesophagitis. Biopsy samples with greater than 15 eosinophils per high powered field in at least two fields were highlighted as possible eosinophilic oesophagitis. The oesophageal biopsies of patients identified in this way were reviewed by a histopathologist with a special expertise in gastroenterology for features suggestive of eosinophilic oesophagitis. RESULTS: Twenty-five thousand three hundred and sixty-five upper gastrointestinal endoscopies were performed between January 2000 and July 2008. A total of 11 072 sets of oesophageal biopsies were taken and 1364 (12.3%) of these revealed evidence of oesophagitis. Only 13 (0.1%) patients had oesophageal biopsies showing greater than 15 eosinophils per high powered field. The median age of this patient group was 23 years (interquartile range 10.5-50.5 years), with 46% of patients under 18 years at the time of diagnosis. The male to female ratio was 5.5 : 1 compared with 1.1 : 1 in the oesophagitis group as a whole, (P=0.002). There was no significant association between endoscopic findings or presenting complaints and the average number of eosinophils per high powered field. The average number of biopsies taken in patients with endoscopic findings suggestive of eosinophilic oesophagitis was 3.75 compared with 1 in patients without those features, (P=0.01). CONCLUSION: Our findings suggest that eosinophilic oesophagitis is a rare disorder predominantly affecting young men.
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Esofagitis Eosinofílica/epidemiología , Adolescente , Adulto , Distribución por Edad , Anciano , Biopsia , Niño , Endoscopía Gastrointestinal , Esofagitis Eosinofílica/diagnóstico , Esofagitis Eosinofílica/patología , Esófago/patología , Femenino , Humanos , Lactante , Irlanda/epidemiología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Distribución por Sexo , Adulto JovenRESUMEN
Achalasia often manifests with dysphagia but can also, albeit less frequently, present more insidiously with unexplained weight loss. We describe the case of a 42-year-old female with Crohn's disease who presented with unexplained weight loss and upper abdominal discomfort. As part of her investigations, a video capsule endoscopy was performed, primarily to assess for small bowel mucosal lesions. This revealed a delay in oesophageal transit time of more than 45 min (normally 2-4 s) giving rise to the discovery of previously undiagnosed achalasia. This was later confirmed by manometry. After subsequent oesophageal dilatation, our patient's weight rose substantially and abdominal discomfort was completely resolved. To our knowledge, this is the first case report of achalasia diagnosed by video capsule endoscopy.