Search

Malaltia de Crohn; Colitis ulcerosa; Vacunació Enfermedad de Crohn; Colitis ulcerosa; Vacunación Crohn's disease; Ulcerative colitis; Vaccination Patients with inflammatory bowel disease (IBD) may require different immunosuppressive treatments throughout their illness. It is essential to assess the immunization status of patients at diagnosis or, if this is not possible, at least before the beginning of immunosuppressive therapy and, subsequently, administering the appropriate vaccines. Therefore, the aim of this work is to establish clear and concise recommendations on vaccination in patients with IBD in the different settings of our clinical practice including vaccination in children, during pregnancy, breastfeeding or on trips. This consensus document emphasises the differences between inactivated and attenuated vaccines and the different degrees of immunosuppression and correlates them with the administration of both mandatory and optional vaccines recommended to our patients with IBD. Finally, as a summary, 17 recommendations are established based on the available scientific evidence and expert opinion. A multidisciplinary team with extensive experience in IBD and vaccination, made up of specialists in gastroenterology, paediatrics, nursing and pharmacy, has participated in the preparation of these recommendations of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis. Los pacientes con enfermedad inflamatoria intestinal (EII) pueden requerir diferentes tratamientos inmunosupresores a lo largo del curso de su enfermedad. Por ello, es fundamental evaluar el estado de inmunización en el momento del diagnóstico o, si no es posible, siempre antes de iniciar un tratamiento inmunosupresor, y administrar las vacunas apropiadas. El objetivo del presente documento es establecer unas recomendaciones claras y concisas sobre la vacunación en pacientes con EII en diferentes escenarios de práctica clínica, incluyendo situaciones especiales como la vacunación en la edad pediátrica, el embarazo, la lactancia o en viajes al extranjero. Se presentan las diferencias entre vacunas inactivadas y atenuadas, los diferentes grados de inmunosupresión y su relación con las pautas de administración de las diferentes vacunas (tanto obligatorias como opcionales) recomendadas a los pacientes con EII. En el documento, se establecen 17 recomendaciones basadas en la evidencia científica disponible y opinión de expertos. En la elaboración de estas recomendaciones del Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa ha participado un equipo multidisciplinar con amplia experiencia en EII y vacunación formado por especialistas de gastroenterología, pediatría, enfermería y farmacia.

Chronic gut inflammation in Crohn’s disease (CD) is associated with an increase in oxidative stress and an imbalance of antioxidant enzymes. We have previously shown that catalase (CAT) activity is permanently inhibited by CD. The purpose of the study was to determine whether there is any relationship between the single nucleotide polymorphisms (SNPs) in the CAT enzyme and the potential risk of CD associated with high levels of oxidative stress. Additionally, we used protein and regulation analyses to determine what causes long-term CAT inhibition in peripheral white mononuclear cells (PWMCs) in both active and inactive CD. We first used a retrospective cohort of 598 patients with CD and 625 age-matched healthy controls (ENEIDA registry) for the genotype analysis. A second human cohort was used to study the functional and regulatory mechanisms of CAT in CD. We isolated PWMCs from CD patients at the onset of the disease (naïve CD patients). In the genotype-association SNP analysis, the CAT SNPs rs1001179, rs475043, and rs525938 showed a significant association with CD (p < 0.001). Smoking CD patients with the CAT SNP rs475043 A/G genotype had significantly more often penetrating disease (p = 0.009). The gene expression and protein levels of CAT were permanently reduced in the active and inactive CD patients. The inhibition of CAT activity in the PWMCs of the CD patients was related to a low concentration of CAT protein caused by the downregulation of CAT-gene transcription. Our study suggests an association between CAT SNPs and the risk of CD that may explain permanent CAT inhibition in CD patients together with low CAT gene and protein expression.

COVID-19 is a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was described in China in late 2019. There are currently more than three million diagnosed cases, constituting a pandemic which has caused a worldwide crisis. The devastating effects of this infection are due to its highly contagious nature and although mild forms predominate, in absolute values, the rates for severe forms and mortality are very high. The information on the characteristics of the infection in inflammatory bowel disease is of special interest, as these patients have higher attendance at health centres, which may increase their risk of infection. Furthermore, the treatments used to control the inflammatory activity may modify the disease course of COVID-19. The Spanish Working Group on Crohn's Disease and Ulcerative Colitis and the Spanish Nurses Working Group on Inflammatory Bowel Disease have prepared this document as a practical response to some common questions about the treatment of these patients. (C) 2020 The Authors. Published by Elsevier Espana, S.L.U.

[Abstract] Objectives: Mobile apps are useful tools in e-health and self-management strategies in disease monitoring. We evaluated the Harvey–Bradshaw index (HBI) mobile app self-administered by the patient to see if its results agreed with HBI in-clinic assessed by a physician. Methods: Patients were enrolled in a 4-month prospective study with clinical assessments at months 1 and 4. Patients completed mobile app HBI and within 48 h, HBI was performed by a physician (gold standard). HBI scores characterized Crohn's disease (CD) as remission

Introducció: En el primer any posterior a una cirurgia intestinal resectiva, un elevat percentatge de pacients amb malaltia de Crohn (EC) desenvolupen lesions inflamatòries mucoses en el neoíleon terminal anastomosado, fenomen que es coneix com a recurrència postquirúrgica (RPQ). Aquest percentatge pot variar entre un 40-70% en funció de si es prescriu o no tractament preventiu posterior a la cirurgia, respectivament. El desenvolupament de lesions recurrents implica un major risc de desenvolupar símptomes i complicacions pròpies de la EC i, per tant, un major risc de requerir noves intervencions quirúrgiques durant el seguiment el que incrementa el risc de pèrdua de la funció intestinal. Objectius: Avaluar la història natural del desenvolupament de RPQ endoscòpica en pacients sota tractament profilàctic de manteniment amb tiopurinas, quan inicialment han previngut l'aparició d'una RPQ endoscòpica precoç en els primers 6-12 mesos després de la cirurgia, i avaluar l'eficàcia dels agents anti-TNF (infliximab o adalimumab) per a la prevenció i tractament de la RPQ endoscòpica després de la cirurgia resectiva intestinal. Mètodes: es van realitzar 3 estudis retrospectius a partir de cohorts de pacients inclosos de manera consecutiva i prospectiva. El primer estudi va ser unicéntrico, en el qual es va incloure tots els pacients amb resecció intestinal i anastomosis ileocólica que van iniciar tractament preventiu amb tiopurinas posterior a la cirurgia, amb una primera avaluació endoscòpica sense RPQ endoscòpica, per a avaluar les proporcions de RPQ en el seguiment. Un segon estudi d'àmbit estatal, multicèntric, en una cohort de pacients identificats a partir del registre ENEIDA, en els quals es va prescriure tractament preventiu de RPQ amb agents anti-TNF (adalimumab o infliximab) dins dels 3 mesos posteriors a la resecció ileocolónica i, tenien una avaluació endoscòpica dins dels 18 mesos posteriors a la cirurgia per a avaluar l'eficàcia dels agents anti-TNF. Finalment, un tercer estudi, multicèntric, en una cohort de pacients amb EC amb resecció intestinal i anastomosis ileocólica, que havien iniciat tractament amb agents anti-TNF (infliximab o adalimumab) posterior al diagnòstic de RPQ endoscòpica establerta (definida per un índex de Rutgeerts >i1), per a avaluar les taxes d'eficàcia dels agents anti-TNF. Conclusions: Les tiopurinas són eficaces a prevenir la RPQ endoscòpica a llarg termini quan han estat efectives en la prevenció de RPQ endoscòpica precoç. Els agents anti-TNF (infliximab i adalimumab), són eficaços a prevenir la RPQ, sense diferències entre tots dos, i també són eficaces a millorar i revertir la RPQ endoscòpica establerta. El tractament concomitant amb tiopurinas i la teràpia amb infliximab s'associen a una major eficàcia terapèutica a revertir lesions mucoses. Introducción: En el primer año posterior a una cirugía intestinal resectiva, un elevado porcentaje de pacientes con enfermedad de Crohn (EC) desarrollan lesiones inflamatorias mucosas en el neoíleon terminal anastomosado, fenómeno que se conoce como recurrencia postquirúrgica (RPQ). Este porcentaje puede variar entre un 40-70% en función de si se prescribe o no tratamiento preventivo posterior a la cirugía, respectivamente. El desarrollo de lesiones recurrentes implica un mayor riesgo de desarrollar síntomas y complicaciones propias de la EC y, por tanto, un mayor riesgo de requerir nuevas intervenciones quirúrgicas durante el seguimiento lo que incrementa el riesgo de pérdida de la función intestinal. Objetivos: Evaluar la historia natural del desarrollo de RPQ endoscópica en pacientes bajo tratamiento profiláctico de mantenimiento con tiopurinas, cuando inicialmente han prevenido la aparición de una RPQ endoscópica precoz en los primeros 6-12 meses tras la cirugía, y evaluar la eficacia de los agentes anti-TNF (infliximab o adalimumab) para la prevención y tratamiento de la RPQ endoscópica tras la cirugía resectiva intestinal. Métodos: se realizaron 3 estudios retrospectivos a partir de cohortes de pacientes incluidos de forma consecutiva y prospectiva. El primer estudio fue unicéntrico, en el que se incluyó todos los pacientes con resección intestinal y anastomosis ileocólica que iniciaron tratamiento preventivo con tiopurinas posterior a la cirugía, con una primera evaluación endoscópica sin RPQ endoscópica, para evaluar las proporciones de RPQ en el seguimiento. Un segundo estudio de ámbito estatal, multicéntrico, en una cohorte de pacientes identificados a partir del registro ENEIDA, en los que se prescribió tratamiento preventivo de RPQ con agentes anti-TNF (adalimumab o infliximab) dentro de los 3 meses posteriores a la resección ileocolónica y, tenían una evaluación endoscópica dentro de los 18 meses posteriores a la cirugía para evaluar la eficacia de los agentes anti-TNF. Por último, un tercer estudio, multicéntrico, en una cohorte de pacientes con EC con resección intestinal y anastomosis ileocólica, que habían iniciado tratamiento con agentes anti-TNF (infliximab o adalimumab) posterior al diagnóstico de RPQ endoscópica establecida (definida por un índice de Rutgeerts >i1), para evaluar las tasas de eficacia de los agentes anti-TNF. Conclusiones: Las tiopurinas son eficaces en prevenir la RPQ endoscópica a largo plazo cuando han sido efectivas en la prevención de RPQ endoscópica precoz. Los agentes anti-TNF (infliximab y adalimumab), son eficaces en prevenir la RPQ, sin diferencias entre ambos, y también son eficaces en mejorar y revertir la RPQ endoscópica establecida. El tratamiento concomitante con tiopurinas y la terapia con infliximab se asocian a una mayor eficacia terapéutica en revertir lesiones mucosas. Introduction: In the first year after ileocecal resection with anastomosis a high percentage of patients with Crohn's disease (CD) develop mucosal inflammatory lesions in the neoterminal ileum, a phenomenon known as postoperative recurrence (POR). This percentage ranges between 40-70% in patients without or with preventive therapy prescribed after surgery, respectively. The development of mucosal lesions involves a greater risk of developing symptoms and complications and a greater risk of requiring new surgical interventions during follow-up, which increases the risk of loss of intestinal function. Aims: To evaluate the natural history of the development of endoscopic POR in patients receiving prophylactic maintenance therapy with thiopurines, when initially they have prevented the appearance of early endoscopic POR in the first 6-12 months after surgery, and to evaluate the efficacy of the anti-TNF agents (infliximab or adalimumab) for the prevention and treatment of endoscopic POR after ileocecal resection with anastomosis. Methods: Three retrospective studies have been performed from cohorts of patients consecutively and prospectively included. The first study included all patients with intestinal resection and ileocolonic anastomosis who started preventive therapy with thiopurines after surgery with a first endoscopic assessment without endoscopic POR, to evaluate the long-term outcomes of POR in these patients. The second study was a multicenter, nationwide study that included a cohort of patients identified from the ENEIDA registry, in whom preventive therapy of POR with anti-TNF agents (adalimumab or infliximab) was prescribed within 3 months after ileocolonic resection and who had an endoscopic assessment within 18 months after surgery, to assess the efficacy of anti-TNF agents. Finally, a third multicenter study included a cohort of patients who had started treatment with anti-TNF agents (infliximab or adalimumab) after the diagnosis of established endoscopic POR (defined by an index of Rutgeerts >i1), to assess the efficacy of anti-TNF agents. Conclusions: Thiopurines are effective in preventing long-term endoscopic POR when they have been effective in preventing early endoscopic POR. Anti-TNF agents (infliximab and adalimumab) are effective in preventing POR, with no differences between the two anti-TNF agents, and are also effective in improving and reverting postoperative mucosal lesions (established POR). Concomitant treatment with thiopurines and infliximab therapy are associated with greater therapeutic efficacy in reverting mucosal lesions.

Malaltia de Crohn; Factors predictius; Ustekinumab Enfermedad de Crohn; Factores predictivos; Ustekinumab Crohn’s disease; Predictive factors; Ustekinumab Ustekinumab has shown efficacy in Crohn’s Disease (CD) patients. To identify patient profiles of those who benefit the most from this treatment would help to position this drug in the therapeutic paradigm of CD and generate hypotheses for future trials. The objective of this analysis was to determine whether baseline patient characteristics are predictive of remission and the drug durability of ustekinumab, and whether its positioning with respect to prior use of biologics has a significant effect after correcting for disease severity and phenotype at baseline using interpretable machine learning. Patients’ data from SUSTAIN, a retrospective multicenter single-arm cohort study, were used. Disease phenotype, baseline laboratory data, and prior treatment characteristics were documented. Clinical remission was defined as the Harvey Bradshaw Index ≤ 4 and was tracked longitudinally. Drug durability was defined as the time until a patient discontinued treatment. A total of 439 participants from 60 centers were included and a total of 20 baseline covariates considered. Less exposure to previous biologics had a positive effect on remission, even after controlling for baseline disease severity using a non-linear, additive, multivariable model. Additionally, age, body mass index, and fecal calprotectin at baseline were found to be statistically significant as independent negative risk factors for both remission and drug survival, with further risk factors identified for remission. This work was supported by Janssen-Cilag Spain. This sponsor had a partial role in study design, analysis, and interpretation of data.

Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) resulting from the interaction of multiple environmental, genetic and immunological factors. CD5 and CD6 are paralogs encoding lymphocyte co-receptors involved in fine-tuning intracellular signals delivered upon antigen-specific recognition, microbial pattern recognition and cell adhesion. While CD5 and CD6 expression and variation is known to influence some immune-mediated inflammatory disorders, their role in IBD remains unclear. To this end, Cd5- and Cd6-deficient mice were subjected to dextran sulfate sodium (DSS)-induced colitis, the most widely used experimental animal model of IBD. The two mouse lines showed opposite results regarding body weight loss and disease activity index (DAI) changes following DSS-induced colitis, thus supporting Cd5 and Cd6 expression involvement in the pathophysiology of this experimental IBD model. Furthermore, DNA samples from IBD patients of the ENEIDA registry were used to test association of CD5 (rs2241002 and rs2229177) and CD6 (rs17824933, rs11230563, and rs12360861) single nucleotide polymorphisms with susceptibility and clinical parameters of CD (n=1352) and UC (n=1013). Generalized linear regression analyses showed association of CD5 variation with CD ileal location (rs2241002CC) and requirement of biological therapies (rs2241002C-rs2229177T haplotype), and with poor UC prognosis (rs2241002T-rs2229177T haplotype). Regarding CD6, association was observed with CD ileal location (rs17824933G) and poor prognosis (rs12360861G), and with left-sided or extensive UC, and absence of ankylosing spondylitis in IBD (rs17824933G). The present experimental and genetic evidence support a role for CD5 and CD6 expression and variation in IBD's clinical manifestations and therapeutic requirements, providing insight into its pathophysiology and broadening the relevance of both immunomodulatory receptors in immune-mediated disorders. This work was supported by Spanish Ministerio de Economía y Competitividad (MINECO, SAF2016-80535-R) and Ministerio de Ciencia e Innovación (MCIN/AEI/10.13039/501100011033, PID2019-106658RB-I00), co-financed by European Development Regional Fund “A way to achieve Europe” ERDF, and Agència de Gestió d’Ajuts Universitaris i de Recerca from Generalitat de Catalunya (2017/SGR/1582). SC-L, MV-dA, CC, AL-P, and EC are recipients of fellowships from Spanish Ministerio de Educación, Cultura y Deporte (FPU15/02897), Spanish MINECO (BES-2014-069237 and BES-2017-082107), Chilean Agencia Nacional de Investigación y Desarrollo (2018-72190154), and European Community Seventh Framework Program (FP7/2007/2013; 229673), respectively. SC-L and JL are recipients of short-term fellowships from European Federation of Immunological Societies-Immunology Letters (EFIS-IL) and Erasmus+ from the European Union, respectively. The ENEIDA registry of GETECCU is supported by Biogen, Janssen, Takeda and Pfizer. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.

The intestinal mucus lines the luminal surface of the intestinal epithelium. This mucus is a dynamic semipermeable barrier and one of the first-line defense mechanisms against the outside environment, protecting the body against chemical, mechanical, or biological external insults. At the same time, the intestinal mucus accommodates the resident microbiota, providing nutrients and attachment sites, and therefore playing an essential role in the host–pathogen interactions and gut homeostasis. Underneath this mucus layer, the intestinal epithelium is organized into finger-like protrusions called villi and invaginations called crypts. This characteristic 3D architecture is known to influence the epithelial cell differentiation and function. However, when modelling in vitro the intestinal host–pathogen interactions, these two essential features, the intestinal mucus and the 3D topography are often not represented, thus limiting the relevance of the models. Here we present an in vitro model that mimics the small intestinal mucosa and its interactions with intestinal pathogens in a relevant manner, containing the secreted mucus layer and the epithelial barrier in a 3D villus-like hydrogel scaffold. This 3D architecture significantly enhanced the secretion of mucus. In infection with the pathogenic adherent invasive E. coli strain LF82, characteristic of Crohn’s disease, we observed that this secreted mucus promoted the adhesion of the pathogen and at the same time had a protective effect upon its invasion. This pathogenic strain was able to survive inside the epithelial cells and trigger an inflammatory response that was milder when a thick mucus layer was present. Thus, we demonstrated that our model faithfully mimics the key features of the intestinal mucosa necessary to study the interactions with intestinal pathogens.

Background and Aims: There is little agreement on the nomenclature and description of Crohn's disease (CD) lesions that can be found in the small and large bowel using capsule endoscopy (CE). We performed a systematic review to identify mucosal lesions that have been described using CE in CD, in both the small bowel and colon, with the aim to make propositions to homogenize such descriptions.Methods: A systematic literature search was conducted using Embase, Medline (OvidSP), and Cochrane Central on August 6, 2019. Clinical studies providing nomenclature and descriptions for small bowel and colonic inflammatory lesions using CE in CD were selected for data collection.Results: In total, 851 articles were included for abstract screening out of which 219 were analyzed for full-text review. Twenty-two articles were selected for data extraction. Seven items, accompanied by clear descriptions, were found for the small bowel: i.e., ulcer, erosion, aphthoid lesion, edema, fissure, cobblestone appearance, and villous atrophy. No studies were found describing inflammatory items using CE in colonic CD.Conclusions: The most frequently described CD lesions using CE were ulcers and erosions. Subjective interpretation of CE inflammatory findings plays an important role. Based on our findings, a range of suggestions regarding items and descriptions is made that might form the basis of a pan-enteric CE activity index.

The gut microbiota (GM) plays a pivotal role in the maintenance of gut homeostasis, and the pathogenesis of inflammatory bowel disease (IBD) which includes Crohn's disease (CD) and ulcerative colitis (UC). The degree of IBD activity, and therefore of inflammation, modifies the composition of the GM towards an altered pattern called dysbiosis This IBD-dysbiosis pattern is different from healthy individuals (HI). The degree of dysbiosis is a good indicator of IBD disease activity and could be useful in monitoring IBD disease activity. The AIM of this study is to quantify the degree of IBD diysbiosi of the GM, and determine the utility as a biomarker for monitoring IBD disease compared with HI. METHODS: 80 prospective IBD patients from a cohort of 2 tertiary hospitals from Catalonia (Girona and Vic) have been included. As a clinical practice study, we included patients with clinical Remission, defined as Fecal Calprotectin (FC) levels 250 µg/gr.) with mild to moderate disease. A blood sample (to determinate RCP, albumin and haemoglobin (Hb) levels) and stool sample (to determinate Faecal calprotectin (FC) and GM analysis) have been collected. Of the fecal samples, DNA was extracted using real-time qPCR) techniques and 3 bacterial groups (Faecalibacterium prausnitzii (FP), Escherichia coli (EC) and total eubacteria (TE), that are highly representative of GM dysbiosis degree, were analyzed. An index called FEI has been created to quantify GM dysbiosis. Data has been collected from Endoscopic IBD index (SES-CD and Mayo score), clinical IBD activity index (HBI and SCCAI) and quality of life index (IBD-Q) along with standard analytical disease activity markers (Hb,PCR,CP and Alb) in order to compare with microbial markers (FEI). The duration of this study is 6 months (every three months samples, T0, T1 and T2)) La microbiota intestinal (MI), entre altres factors, desenvolupa un paper clau en el manteniment de l’homeòstasi intestinal i la patogènesi de la malaltia inflamatòria intestinal (MII) que inclou la Malaltia de Crohn (MC) i la Colitis ulcerosa (CU). L’activitat de la MII, i conseqüentment de la inflamació intestinal, modifica la composició de la MI en un patró alterat respecte dels control sans (CS) anomenat disbiosi. Aquest grau de disbiosi és un bon indicador de l’activitat de la MII i pot ser utilitzat pel seu monitoratge. L’objectiu de la present tesi és la quantificació del grau de disbiosi de la MI per determinar-ne la utilitat com a biomarcador per monitorar l’activitat de la MII respecte dels CS. Es van incloure prospectivament 80 pacients amb MII d’una cohort de 2 hospital terciaris de Catalunya (Girona i Vic). Com a estudi de pràctica clínica, es van incloure pacients en remissió clínica (Rem), definida per un valor de la Calprotectina fecal (CP) 250 µg/gr) i que presentaven malaltia de lleu a moderada. Es van recollir mostres de sang (per determinar PCR, Albúmina i Hemoglobina (Hb)) i una fecal (per a determinar nivells de CP i quantificar la MI). S’ha quantificat mitjançant tècniques de qPCR en temps real el DNA bacterià de 3 grups bacterians (Faecalibacterium prausnitzii (FP), Escherichia coli (EC) i els eubacteris totals (ET)) altament representatius del grau de disbiosi de la MI. La relació entre FP i EC es calcula a través de un índex anomenat FEI (relació FP/EC) que quantifica de manera simple el grau de disbiosi de la MI. Es van recollir dades dels índex endoscòpics de la MII (SES-CD i Índex de Mayo), d’activitat (HBI i SCCAI) i de qualitat de vida (IBD-Q) i els marcadors habituals d’activat (Hb, PCR,CP i Alb) per comparar amb els indicadors microbiològics (FEI). El període de seguiment va ser de 6 mesos amb mostres cada 3mesos (T0, T1 i T2) Programa de Doctorat en Biologia Molecular, Biomedicina i Salut

Background: Multiple studies have described the effectiveness of ustekinumab (UST) and vedolizumab (VDZ) in patients with Crohn’s disease (CD) failing anti- Tumor necrosis factors (TNFs), however, the effectiveness of VDZ or UST as a third-class biologic has not yet been described. Aims and Methods: In this retrospective multicenter cohort study, we aimed to investigate the effectiveness of VDZ and UST as a third-class biologic in patients with CD. Results: Two-hundred and four patients were included, 156/204 (76%) patients received VDZ as a second- and UST as a third-class therapy (group A), the remaining 48/204 (24%) patients received UST as a second- and VDZ as a third-class therapy (group B). At week 16–22, 87/156 (55.5%) patients and 27/48 (56.2%) in groups A and B, respectively, responded to treatment (p = 0.9), 41/156 (26.2%) and 15/48 (31.2%) were in clinical remission (p = 0.5). At week 52, 89/103 (86%) patients and 25/29 (86.2%) of the patients with available data had responded to third-class treatment in groups A and B, respectively (p = 0.9), 31/103 (30%) and 47/29 (24.1%) were in clinical remission (p = 0.5). Conclusion: Third-class biological therapy was effective in more than half of the patients with CD. No differences in effectiveness were detected between the use of VDZ and UST as a third-class agent.

Diet may influence the development of inflammatory bowel disease through the modulation of inflammation. We investigated whether the inflammatory potential of the diet is associated with the risk of Crohn’s disease (CD) and ulcerative colitis (UC) in the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Spain). The study included 32,633 participants aged 29–69 years. The inflammatory potential of the diet was measured by using an inflammatory score of the diet (ISD) based on a baseline dietary history questionnaire. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During 21 years (674,547 person-years) of follow-up, 32 and 57 participants developed CD and UC, respectively. In multivariable analysis, a one-standard deviation (SD) increment in the ISD (two-unit increase) was associated with a higher risk of CD (HR of 1.71; 95% CI: 1.05–2.80; p = 0.031). By contrast, ISD was not associated with UC (HR for one-SD increment of 0.89; 95% CI: 0.66–1.19; p = 0.436). Our results suggest that consuming a more pro-inflammatory diet may contribute to the risk of CD, supporting that a healthy diet might be beneficial in its prevention. Further, larger studies are needed to verify these findings., Instituto de Salud Carlos III (PIE14/00045), Crohn’s and Colitis UK (M2017-2), e Intra-CIBERESP mobility program (ESPF60/2017), International Agency for Research on Cancer (IARC), Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, NIHR Imperial Biomedical Research Centre (BRC), Health Research Fund (FIS)-Instituto de Salud Carlos III (ISCIII), e Regional Governments of Andalusia, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology-ICO (Spain)

Introducción: La Enfermedad Inflamatoria Intestinal (EII) es una patología crónica que afecta tanto al paciente como a su entorno en todos los ámbitos: físico, psicológico y social. El desconocimiento de esta enfermedad y un mal estilo de vida agravan su evolución. Las intervenciones de enfermería pueden ayudar a mejorar la calidad de vida de estos pacientes mediante una educación sanitaria con modificaciones higiénico-dietéticas, proporcionando apoyo físico y psicológico tanto al paciente como a su entorno familiar. Objetivos: Valorar si las intervenciones de enfermería de un programa educativo mejoran la calidad de vida percibida por el paciente con EII. Material y métodos: Se trata de un estudio prospectivo de cohortes longitudinal en pacientes entre 18 y 70 años diagnosticados con EII de las consultas del Hospital Universitari Santa María de Lleida. Se evaluara si estas intervenciones permiten constatar un aumento en la calidad de vida por el cuestionario IBDQ-32, de la fatiga por la escala EIDF, y la mejoría de los síntomas con la escala CDAI en Enfermedad de Crohn y Truelove en Colitis Ulcerosa, antes y después de la realización de un programa educativo de enfermería. La duración es de 3 meses: el primer mes se reclutaran un máximo de 20 pacientes (por limitaciones de espacio en el aula), en ese momento se pasaran los cuestionarios para medir las variables inicialmente, posteriormente se impartirán 4 sesiones grupales de 1 hora cada sábado durante un mes y al mes siguiente se realizará la evaluación final, pasándose nuevamente los cuestionarios para ver si hay cambios significativos tras el programa. Las sesiones se dedicaran al conocimiento de la enfermedad, medidas higiénico dietéticas y adherencia al tratamiento para intentar promover el autocuidado y disminuir el estrés, aportando conocimientos básicos de su enfermedad y apoyo emocional individualizado por parte de enfermería. Introducció: La Malaltia Inflamatòria Intestinal (MII) és una patologia crònica que afecta tant al pacient com al seu entorn en tots els àmbits: físic, psicològic i social. El desconeixement d'aquesta malaltia i un mal estil de vida agreugen la seva evolució. Les intervencions d'infermeria poden ajudar a millorar la qualitat de vida d'aquests pacients mitjançant una educació sanitària amb modificacions higienicodietètiques, proporcionant suport físic i psicològic tant al pacient com al seu entorn familiar. Objectius: Valorar si les intervencions d'infermeria d'un programa educatiu milloren la qualitat de vida percebuda pel pacient amb MII. Material i mètodes: Es tracta d'un estudi prospectiu de cohorts longitudinal en pacients entre 18 i 70 anys diagnosticats amb MII de les consultes de l'Hospital Universitari Santa María de Lleida. Es avalués si aquestes intervencions permeten constatar un augment en la qualitat de vida pel qüestionari IBDQ-32, de la fatiga per l'escala EIDF, i la millora dels símptomes amb l'escala CDAI en Malaltia de Crohn i Truelove en Colitis Ulcerosa, abans i després de la realització d'un programa educatiu d'infermeria. La durada és de 3 mesos: el primer mes es reclutessin un màxim de 20 pacients (per limitacions d'espai a l'aula), en aquest moment es passessin els qüestionaris per mesurar les variables inicialment, posteriorment s'impartiran 4 sessions grupals d'1 hora cada dissabte durant un mes i a el mes següent es realitzés l'avaluació final, passant-nou els qüestionaris per veure si hi ha canvis significatius després el programa. Les sessions es dedicaran a el coneixement de la malaltia, mesures higienicodietètiques i adherència a el tractament per intentar promoure l'autocura i disminuir l'estrès, aportant coneixements bàsics de la seva malaltia i suport emocional individualitzat per part d'infermeria. Introduction: Inflammatory Bowel Disease (IBD) is a chronic pathology that affects both the patient andtheir environment in all areas: physical, psychological and social. The ignorance of this disease and a bad lifestyle aggravate their evolution. Nursing interventions can help improve the quality of life of these patients through health education with hygienic-dietary modifications, providing physical and psychological support to both the patient and their family environment. Objectives: To assess whether nursing interventions in an educational program improve the quality of life perceived by the patient with IBD. Material and methods: This is a prospective longitudinal cohort study in patients between the ages of 18 and 70 diagnosed with IBD at the Hospital Universitari Santa Maria de Lleida. We evaluated whether these interventions show an increase in quality of life by the IBDQ-32 questionnaire, fatigue by the EIDF scale, and improvement of symptoms with the CDAI scale in Crohn's disease and Truelove in Ulcerative Colitis, before and after the completion of an educational nursing program. The duration is 3 months: the first month, a maximum of 20 patients will be recruited (due to space limitations in the classroom), at that time the questionnaires willbe passed to measure the variables initially, afterwards 4 group sessions of 1 hour will be given every Saturday for a month and the following month the final evaluation will be carried out, passing the questionnaires again to see if there are significant changes after the program. The sessions will be devoted to knowledge of the disease, hygienic dietary measures and adherence to treatment to try to promote self-care and reduce stress, providing basic knowledge of your disease and individualized emotional support from the nursing staff.

The tumor necrosis factor (TNF) acts as a potent inducer of inflammation in autoimmune diseases like Crohn disease and ulcerative colitis. Current available treatments are based on TNF inhibition such as infliximab and adalimumab. These drugs are very effective in inducing and maintaining remission. However, there is a high proportion of patients that lose their initial response over time. Recently, some studies have used therapeutic anti-TNF monitoring tools in order to adjust treatments according to each patient. We have conducted a prospective multicenter study to determine the usefulness of therapeutic anti-TNF monitoring in patients with Crohn disease or ulcerative colitis in two centers with a different degree of specialization. The results have allowed us to assess the clinical and economic impact of therapeutic anti-TNF monitoring in each center. Moreover, they have let us to determine which variables might influence the pharmacokinetics of these anti-TNF drugs El factor de necrosi tumoral (TNF) actua com un potent inductor de la inflamació en la malaltia de Crohn (MC) i colitis ulcerosa (CU). Pel tractament d’aquestes malalties existeixen fàrmacs anti-TNF com Infliximab i Adalimumab, medicaments efectius per induir i mantenir la remissió encara que una alta proporció de pacients deixen de respondre al llarg del temps. Darrerament, alguns estudis han començat a utilitzar l’eina de la determinació de nivells de fàrmac per ajustar les pautes de tractament en funció de cada pacient. Durant aquesta tesi doctoral hem realitzat un estudi pilot multicèntric prospectiu per determinar la utilitat del monitoratge farmacocinètic de fàrmacs anti-TNF en pacients amb MC o CU en dos centres amb diferent grau d’especialització. Els resultats ens han permès determinar l’impacte clínic i econòmic que representa el monitoratge farmacocinètic de fàrmacs anti-TNF a cada hospital i determinar les variables que afecten a la farmacocinètica d’aquests fàrmacs

El registro ENEIDA, promovido por el Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU), fue creado en 2005 por un grupo de gastroenterólogos interesados en mejorar el manejo de los pacientes con enfermedad inflamatoria intestinal. Los objetivos principales del registro fueron facilitar la recogida de datos clínicos de interés para la práctica clínica asistencial, así como la elaboración de estudios colaborativos a partir de datos clínicos y muestras biológicas. En sus 15 años de existencia, ENEIDA ha evolucionado en múltiples aspectos, desde su contenido o su soporte tecnológico hasta el número de centros participantes, para convertirse en uno de los registros de referencia para el estudio y cuidado de los pacientes con enfermedad inflamatoria intestinal, con una producción científica continua y de alta calidad que lo ha situado como ejemplo de explotación científica colaborativa en el ámbito internacional. En este artículo se revisan los objetivos, el diseño, las características estructurales, la monitorización y la explotación científica del registro ENEIDA, The ENEIDA registry, promoted by the Spanish Working Group on Crohn’s Disease andUlcerative Colitis (GETECCU), was created in 2005 by a group of gastroenterologists interested inimproving the management of patients with inflammatory bowel disease. The main objectives ofthe registry were to facilitate the collection of clinical data of interest for clinical care practice,as well as to carry out collaborative studies using clinical data and biological samples. In its15 years of existence, ENEIDA has evolved in many aspects, from its content or technologicalsupport to the number of participating centres, to become one of the reference registries forthe study and care of patients with inflammatory bowel disease, with a continuous and highquality scientific production that has positioned it as an example of collaborative scientificexploitation at an international level. This article reviews the objectives, design, structuralcharacteristics, monitoring and scientific exploitation of the ENEIDA registry.

Extraintestinal manifestations, in general, and in particular arthropathies, are a common problem in patients with inflammatory bowel disease. In fact, the relationship between those 2 entities is close and there are increasingly more data which suggest that the bowel plays a significant role in the aetiopathogenesis of spondyloarthritis. The association of inflammatory bowel disease with any kind of spondyloarthritis represents a challenging clinical scenario. It is therefore necessary that both gastroenterologists and rheumatologists work together and establish a fluent communication that enables the patient to receive the most appropriate treatment for each specific situation. The aim of this review is to make some recommendations about the treatment of patients with inflammatory bowel disease and associated spondyloarthritis, in each different clinical scenario., Las manifestaciones extraintestinales en general, y entre ellas las articulares en particular, suponen un problema frecuente en los pacientes con enfermedad inflamatoria intestinal. De hecho, la relación entre ambas entidades parece estrecha y cada vez hay más datos que sugieren que el intestino desempeña un importante papel en la patogenia de las espondiloartritis. La asociación de la enfermedad inflamatoria intestinal con algún tipo de espondiloartritis supone un escenario clínico complejo. Es necesario, por tanto, que gastroenterólogos y reumatólogos puedan trabajar juntos y establecer una comunicación fluida que permita a cada paciente recibir el tratamiento más adecuado para cada situación concreta. El objetivo de esta revisión es el de establecer unas recomendaciones sobre el tratamiento de los pacientes con enfermedad inflamatoria intestinal y espondiloartritis asociada, en cada uno de los distintos escenarios clínicos

Ferrer-Picón et al. show that in active IBD patients, tumor necrosis factor alpha affects the response of the intestinal epithelium to bacteria-derived butyrate. This observation raises questions about the beneficial effects of butyrate supplementation during active inflammation., Background Butyrate-producing gut bacteria are reduced in patients with active inflammatory bowel disease (IBD), supporting the hypothesis that butyrate supplementation may be beneficial in this setting. Nonetheless, earlier studies suggest that the oxidation of butyrate in IBD patients is altered. We propose that inflammation may decrease epithelial butyrate consumption. Methods Non-IBD controls and IBD patients were recruited for the study. Stool samples were used for short-chain fatty acid and bacterial butyryl CoA:acetate CoA-transferase quantification. Colonic biopsies and ex vivo differentiated epithelial organoids (d-EpOCs) treated with butyrate and/or tumor necrosis factor alpha (TNFα) were used for analyzing the expression of transporters MCT1 and ABCG2, metabolic enzyme ACADS, and butyrate receptor GPR43, and for butyrate metabolism and consumption assays. Results We observed that lower stool content of butyrate-producing bacteria in active IBD patients did not correlate with decreased butyrate concentrations. Indeed, the intestinal epithelial expression of MCT1, ABCG2, ACADS, and GPR43 was altered in active IBD patients. Nonetheless, d-EpOCs derived from IBD patients showed SLC16A1 (gene encoding for MCT1 protein), ABCG2, ACADS, and GPR43 expression levels comparable to controls. Moreover, IBD- and non-IBD-derived d-EpOCs responded similarly to butyrate, as assessed by transcriptional regulation. TNFα significantly altered SLC16A1, ABCG2, and GPR43 transcription in d-EpOCs, mimicking the expression profile observed in biopsies from active IBD patients and resulting in reduced butyrate consumption. Conclusions We provide evidence that the response to butyrate is not intrinsically altered in IBD patients. However, TNFα renders the epithelium less responsive to this metabolite, defeating the purpose of butyrate supplementation during active inflammation.

[eng] Crohn’s disease [CD] is a chronic inflammatory disease of the intestinal tract with considerable heterogeneity among affected patients in terms of disease phenotype and therapeutic responses. Despite the increase in the number of drugs approved for the management of CD, a significant percentage of patients remain unresponsive or lose response over time to treatments, and eventually require surgery to control disease activity and/or complications. Nonetheless, in a fraction of these refractory patients, intestinal resection may not be possible due to disease location, extension or previous surgeries. For such patients, autologous hematopoietic stem cell transplantation [HSCT] represents a potential salvage therapy despite the risks associated with this procedure. Stem cell transplantation is an accepted therapy for hematological disorders, aplastic anemia and immunodeficiencies. In the context of autoimmune diseases, the serendipitous benefits of transplantation were initially reported in patients suffering from both immune-mediated diseases and hematological disorders. This led to trials that have shown the efficacy of autologous HSCT in treating an array of autoimmune diseases including refractory severe multiple sclerosis, systemic lupus erythematosus, juvenile idiopathic arthritis, rheumatoid arthritis and, more recently, CD. The benefit of HSCT in autoimmunity is thought to originate from the ability of intense immune depletion to eliminate auto-reactive cells regardless of their specificity. This would lead to de novo generation of immune cells that could re-establish tolerance, although no objective evidence of this ‘resetting’ has been reported thus far. To explore this hypothesis, we group of CD patients [n = 18] receiving autologous HSCT, with 50% of them achieving endoscopic drug-free remission. To elucidate the mechanisms driving efficacy, we monitored changes after HSCT in blood and intestine immune-cell composition. CD patients [n = 22] receiving anti-tumor necrosis factor [TNF]-α were included for comparison. Severe immune ablation followed by HSCT induced dramatic changes in both peripheral blood T and B cells in all patients regardless of the efficacy of the treatment. Endoscopic remission at week 52 following HSCT was associated with significant intestinal transcriptional changes. A comparison of the remission signature with that of anti-TNFα identified both common and unique genes in the HSCT-induced response. Based on deconvolution analysis of intestinal biopsy transcriptome data, we show that response to HSCT, but not to anti-TNFα, is associated with an expansion of naïve B-cells, as seen in blood, and a decrease in the memory resting T- cell content. As expected, endoscopic remission, in response to both HSCT and anti-TNFα, led to a significant reduction in intestinal neutrophil and M1 macrophage content. HSCT dramatically renewed the pre-existing T-cell receptor [TCR] repertoire; however, persistent high-frequency TCR clones were detected in all patients in both blood and biopsy throughout the first year of follow-up. The number of persistent resident T cell clonotypes in tissue after treatment decreased in patients that achieve endoscopic remission. Furthermore, we found that low TCR peripheral diversity at baseline, and up to 1 year after HSCT, were associated with a lack of response to the immunoablative protocol. Peripheral blood immune remodeling after HSCT does not predict efficacy. In contrast, a profound intestinal T-cell depletion that is maintained long after transplant is associated with mucosal healing following HSCT, but not anti-TNFα., [spa] Se ha demostrado la eficacia del trasplante hematopoyético de células madre (THCM) en pacientes con enfermedad de Crohn severamente refractaria. La hipótesis aceptada es que el proceso de THCM elimina células auto-reactivas, devolviendo así la tolerancia. No obstante, no existen estudios específicos y exhaustivos sobre la reconstitución inmune en pacientes con enfermedad de Crohn tratados con THCM. En esta tesis, monitorizamos una cohorte de 18 pacientes con enfermedad de Crohn refractaria que recibieron trasplante autólogo de células madre hematopoyéticas, de los cuales el 50% consiguieron la remisión endoscópica sin tratamiento de mantenimiento. Para elucidar los mecanismos que determinan la eficacia, monitorizamos los cambios después de THCM en la composición de células inmunes tanto en sangre como en tejido intestinal. Como resultado, observamos que la ablación inmune producida durante el TCMH induce cambios dramáticos en las células T y B en sangre en todos los pacientes, independientemente de la eficacia del tratamiento. La remisión endoscópica en la semana 52 posterior al TCMH se asoció con cambios transcripcionales intestinales significativos. Una comparación de la transcripción en remisión con la de la remisión inducida por fármaco identificó genes comunes y únicos en la respuesta inducida por el TCMH. A través de un análisis de deconvolución de los datos del transcriptoma de la biopsia intestinal, mostramos que la respuesta al TCMH, pero no a fármaco inmuno- modulador, se asocia con una expansión de las células B naïve y una disminución en el contenido de células T memoria. Como se esperaba, la remisión endoscópica, en respuesta a tanto a TCMH como a fármaco, condujo a una reducción significativa en el contenido de neutrófilos intestinales y macrófagos M1 La remodelación inmune de la sangre periférica después del TCMH no predice la eficacia. No obstante, la depleción de las células T intestinales mantenida un año después del trasplante se asocia con la curación mucosa después del TCMH.

The adherent-invasive Escherichia coli (AIEC) pathotype could play a role in the course of Crohn’s disease. This is characterized by its capacity to adhere to and to invade intestinal epithelial cells as well as to replicate and survive within macrophages. At present, identification of the AIEC pathotype relies on time-consuming techniques based on the phenotypic screening of cultured bacteria, which are not standardized. In this thesis, we focused on the study of AIEC genetics in order to look for key characteristics that could assist the development of a molecular tool for the identification of the pathotype. To sum up, the results of this work provide meaningful information that contributes to our understanding of AIEC genomics. In this case, two putative molecular markers resulting from a combination of genetic and/or phenotypic features have been presented and these could assist in AIEC screening. Finally, gene expression results provide new insights to better describe genes putatively involved in AIEC virulence El patotip adherent-invasiu d’Escherichia coli (AIEC) podria jugar un paper en el transcurs de la malaltia de Crohn. Aquest es caracteritza per tenir capacitat d’adhesió i invasió a cèl·lules de l’epiteli intestinal a més de replicar-se i sobreviure en macròfags. Actualment la única manera d’identificar aquests bacteris és analitzant aquestes característiques fenotípiques, un mètode poc estandarditzat i que requereix molt temps i dedicació. En la present tesi ens hem centrat en estudiar genèticament el patotip AIEC per tal de buscar característiques clau que puguin ajudar en el desenvolupament d’una eina molecular per a la seva identificació. En resum, els resultats d'aquest treball proporcionen informació significativa que contribueix a la comprensió de la genètica del patotip AIEC. En aquest cas, s'han presentat dos possibles marcadors moleculars resultants d'una combinació de característiques genètiques i/o fenotípiques que podrien ajudar en la detecció d’AIEC. Finalment, els resultats d'expressió gènica proporcionen noves idees per descriure millor els gens implicats en la virulència del patotip AIEC Programa de Doctorat en Biologia Molecular, Biomedicina i Salut

[spa] La enfermedad de Crohn (EC) es una enfermedad Inflamatoria que puede afectar a cualquier parte del tracto digestivo. Aunque su etiología no está del todo clara, la hipótesis prevalente indica que se produce a causa de una pérdida de tolerancia contra la mlcrobiota comensal. La presencia de anticuerpos en el suero en un porcentaje importante de los pacientes con EC refuerza esta hipótesis. Esto sugiere que debe existir una respuesta T específica contra la microbiota comensal. No obstante, aunque las células T son consideradas uno de los elementos más importantes en la patogénesls de la EC, su especificidad antlgénlca y su naturaleza no se han estudiado con profundidad. En el primer estudio se demuestra la existencia de células T memoria especificas para diferentes antígenos de la mlcroblota comensal en Individuos sanos y en pacientes con EC. Las células presentes en los enfermos presentan una mayor capacidad prollferatlva. Además, las células T CD4+ específicas para 3 proteínas de la mlcroblota comensal (FlaX, A4-fla2 y YldX), presentan un perfil Th17/Th1 únicamente en los pacientes con EC. Esta respuesta caracterizada por la producción de IL-17A, IL-17F, IL-22, CCL20, IFN-y y TNF-o promueve la sobreexpreslón de qulmloclnas capaces de atraer a células Thl 7 y a neutrófilos, siendo un mecanismo para amplificar y mantener la Inflamación en estos pacientes. En el segundo estudio se testó un antagonista de RORyt (81119) que Inhibe de manera específica la transcripción de los genes relacionados con la vía Th17 en las PBMCs estimuladas con los antígenos derivados de la mlcroblota comensal. Sin embargo, este lnhlbidor ocasiona una sobreexpreslón de los genes relacionados con la vía de las células Treg pero preserva las respuestas Thl y Th2. Por otro lado, las criptas Intestinales que se hablan cultivado con los sobrenadantes que provenían de los linfocitos T CD4+ que se hablan tratado con el lnhlbldor, muestran una menor expresión de CXCLl, CXCL8 y CCL20. Además, el 81119 reduce significativamente la transcripción de Ill 7 y de IL26 en muestras que provienen de colon y de íleon de pacientes con EC, sin afectar la transcripción de IL22. El 81119 muestra un efecto más Intenso en las muestras fleales, ya que la expresión de los genes IL23R, CSF2, CXCL1, CXCL8 y S100A8 disminuye en presencia del antagonista, mientras que la expresión de DEFAS aumenta. Finalmente, el B1119 es capaz de reducir los marcadores cllnlcos, macroscópicos y moleculares de la colitis en un modelo experimental de esta enfermedad. Asl pues, nuestros resultados muestran fa existencia de una respuesta T memoria contra la mlcrobiota comensal, así como también apoyan el desarrollo clínico de fármacos inhlbldores de RORyt para modular la vla Th17 en la EC.

Actualmente, el manejo de la enfermedad inflamatoria intestinal (EII) se basa en la evaluación objetiva de las lesiones intestinales. Por ello, es de interés disponer de herramientas sencillas y no invasivas con las que monitorizar la actividad de la EII e identificar la presencia de lesiones. La calprotectina fecal (CF) constituye la principal proteína citosólica de los neutrófilos, es resistente a la degradación bacteriana y estable a temperatura ambiente durante días, características que la hacen adecuada para su uso en la práctica clínica. Es útil para diferenciar entre procesos inflamatorios y funcionales, se correlaciona con la actividad endoscópica, se asocia con la respuesta clínica y endoscópica al tratamiento y tiene valor pronóstico a corto plazo. El presente documento pretende ofrecer una visión actualizada sobre la información que la CF puede proporcionar al clínico en el diagnóstico, la monitorización y el manejo de la EII.

Tutora: Esther Cabrera La Enfermedad de Crohn (EC) es una patología incluida dentro de la categoría de las Enfermedades Inflamatorias Intestinales (EII). Su incidencia se ha incrementado en los últimos años y se considera una enfermedad de los países desarrollados. Cursa con una sintomatología muy variada, pero generalmente siempre están presentes: diarrea crónica, dolor abdominal y pérdida de peso. Se caracteriza por tener periodos de actividad y de remisión. En ocasiones puede venir acompañada de complicaciones o manifestaciones extraintestinales (MEI). Esta patología tiene un gran impacto en la vida de la persona, supone un cambio en su vida. La atención enfermera en los pacientes con EC es necesaria durante todo el proceso de la enfermedad. Objetivo principal: determinar el rol que ejerce la enfermera en estos pacientes. Metodología: es una revisión de la literatura exhaustiva. La búsqueda de ha realizado en los metabuscadores Google Schoolar y Medline, y en las bases de datos Cuiden, Scielo, Fisterra y Cochrane Plus. Se seleccionaron todas las publicaciones escritas desde 2007 en catalán, castellano e inglés. Se descartaron aquellas cuyas hipótesis no se basaran en la ciencia. Conclusión: El papel de enfermería es muy importante en esta patología ya que está presente durante todas las fases de la enfermedad.

La malaltia de Crohn (MC) és un terme que forma part de les malalties inflamatòries intestinals, caracteritzades per una inflamació crònica del tub digestiu cursant amb períodes d’exacerbació i recidives. La incidència de la MC, ha anat en augment en les últimes dècades sobretot en països desenvolupats. Diagnosticant-se de 6 a 9 casos nous per cada 100.000 habitants a l’any. Aquest grup de pacients presenten manifestacions que provoquen gran afectació al seu benestar personal, repercutint a la seva qualitat de vida. Aquesta repercussió es veurà reforçada si amb aquesta patologia base se li suma un estat de descompensació com és l’estat d’embaràs. El paper de la infermeria en el seguiment i control d’aquests pacients com a principal responsable dels seus cuidatges és fonamental. Buscant una atenció de qualitat completa i coordinada a nivell multidisciplinari. És important que les intervencions d’infermeria vagin encaminades a satisfer les necessitats dels pacients, per millorar l’atenció assistencial i qualitat de vida dels pacients. Per tot això, es planteja un programa d’atenció multidisciplinar posant especial èmfasi al control rutinari i a les intervencions d’infermeria, així com l’existència d’una figura coordinadora de les actuacions de les diferents disciplines.

Treballs Finals de Grau de l'Escola Universitària d'Infermeria, Universitat de Barcelona, Curs: 2015-2016, Tutor: Julia Reiriz Palacios, Introducción: La enfermedad de Crohn (EC) es una patología idiopática crónica que cursa con una inflamación del tracto gastrointestinal. Los pacientes tienen síntomas como la diarrea, dolor abdominal, cansancio y fatiga. Produce limitaciones en las áreas físicas, psicológicas, familiares y sociales de la persona y su calidad de vida se ve disminuida drásticamente. Objetivos: Determinar las intervenciones de enfermería que pueden ayudar a mejorar la calidad de vida de los pacientes con Enfermedad de Crohn. Metodología: Revisión bibliográfica en la que se utilizaron las bases de datos PubMed, Cinahl, Cuidatge, SciELO, CUIDEN PLUS y Biblioteca Cochrane Plus. Resultados: Se escogieron un total de 15 artículos según los criterios previamente establecidos. Conclusiones: Enfermería puede ayudar a mejorar la calidad de vida de los pacientes con Enfermedad de Crohn mediante una atención holística, la educación sanitaria, la modificación de estilos de vida (entre ellos, el tabaco, la dieta, el estrés y la prevención de infecciones), la gestión de la sintomatología y proporcionando apoyo físico, psíquico y emocional al paciente y a la familia.

In this PhD thesis Faecalibacterium prausnitzii populations of patients with gut disease and healthy individuals have been characterized. First, isolates from healthy volunteers have been phenotypically characterised, which has allowed to gain insight into the physiology of this species. A possible link between F. prausnitzii sensitivity to changes in gut physicochemical conditions and its disappearance in a diseased gut has been revealed. Second, molecular studies on F. prausnitzii populations have allowed to define two phylogroups within this species, and to describe the diversity of phylotypes in healthy individuals and in patients with intestinal disease. The phylotypes specifically compromised in patients suffering some gut disorders have been identified. Finally, new molecular tools for the detection and quantification of this species and its phylogroups have been designed. Their usefulness to be implemented as complementary molecular tools for the diagnosis and prognosis of intestinal diseases has been determined., En aquesta tesi doctoral s'ha estudiat la població de Faecalibacterium prausnitzii de pacients amb malalties intestinals i individus sans. En primer lloc, es va realitzar una caracterització fenotípica d'aíllats d'aqueta espècie obtinguts d'individus sans, el que ha permès adquirir coneixement sobre la fisiologia d'aquesta espècie. S'ha evidenciat una possible relació entre la sensibilitat de F.prausnitzii a canvis en les condicions fisicoquímiques de l'intestí i la seva desaparició en un intestí malalt. En segon lloc, s'han realitzat estudis moleculars de les poblacions de F. prausnitzii. Això ha permès definir dos filogrups dins d'aquesta espècie, i descriure la diversitat de filotips en individus sans i pacients amb malalties intestinals.Per primera vegada, s'han identificat els filotips especificament compromesos en pacients que pateixen determinades malalties intestinals. Per últim, s’han dissenyat eines moleculars per a la detecció i quantificació d'aquesta espècie i els seus filogrups. S’ha determinat la utilitat d’aquestes eines moleculars per al suport al diagnòstic o prognòstic de malalties intestinals.

The quality of life of a significant proportion of IBD patients is poor as a result of persistent disease activity and repeated surgery, among others. Current treatments for Crohn’s disease are not able to neither prevent this serious impact nor improve the long term prognosis of a significant proportion of patients. Therefore, new therapeutic approaches are needed in order to modify the immune response of these patients. We hypothesize that administration of ex-vivo generated autologous tol-DCs to Crohn’s disease patients may arrest Th1 lymphocyte proliferation and therefore may restore specific tolerance against non-pathogenic antigens in the gut. The overall objective of this thesis was to generate and characterize tol-DCs for the purpose of implementing an autologous immunotherapy treatment for Crohn’s disease patients. In the first study, we described the generation of tol-DCs from healthy donors and Crohn’s disease patients by use of clinical-grade reagents in combination with dexamethasone as immunosuppressive agent and characterized their functional properties. Our main findings demonstrated that the combination of dexamethasone with a specific cytokine cocktail yields clinical-grade DCs with the following characteristics: a semi-mature phenotype, a pronounced shift towards anti-inflammatory versus inflammatory cytokine production and low T-cell stimulatory properties. This characteristic tolerogenic profile is maintained when tol-DCs are activated using heat-inactivated Gram-negative bacteria as maturative stimulus. Whole microorganisms contain multiple PAMPs capable of stimulating DCs by different pathways. Our results clearly showed a strong inhibitory effect on DC phenotype, a robust inhibition of pro-inflammatory cytokines, increased IL-10 secretion, and inhibition of T-cell proliferation and Th1 induction. Interestingly, we showed that tol-DCs have reduced immunogenic capacity in autologous, allogeneic and antigen-specific T-cell responses. We further evaluated the ability of tol-DCs to induce CD4+ T-cell hypo-responsiveness. Our results demonstrated that T-cells or antigen-specific T-cells previously cultured with tol-DCs are anergic exhibiting a reduced capacity to proliferate as well as reduced IFN-gamma secretion when rechallenged with fully competent mDCs. With regard to tol-DCs clinical application, we importantly found that their tolerogenic properties remain stable after washing out dexamethasone and subsequent restimulation with LPS, CD40L or different Gram-negative enterobacteria strains. All these properties led us to conclude that this cell product is suitable to be tested in clinical trials of immune-based diseases such as Crohn’s disease. We further identified a positive biomarker for tol-DCs, MERTK receptor is highly expressed on clinical grade dexamethasone-induced human tol-DCs and contributes in their tolerogenic properties. Our results demonstrated that MERTK expression in human DCs is regulated by glucocorticoids and described a new function of this receptor in directly regulating T-cell response. Interestingly, our findings showed that neutralization of MERTK with monoclonal antibodies in allogeneic MLR cultures leads to increased T-cell proliferation and IFN-gamma production. The direct regulation of T-cell response was confirmed by the use of recombinant MERTK-Fc protein, used to mimic MERTK on DCs. Our results remarkably showed that MERTK-Fc suppresses naïve and antigen-specific memory Tcell proliferation and activation. These findings identified a new non-cell autonomous regulatory function of MERTK expressed on DCs. Additionally, we described that this regulation is mediated by the neutralization of MERTK soluble ligand PROS1. We also found that MERTK is expressed on T-cell surface and that PROS1 drives an autocrine pro-proliferative effect on these cells. In summary, the results of this work demonstrated that MERTK on DCs regulates T-cell activation and expansion through the competition for PROS1 interaction with MERTK in the T-cells. We showed that MERTK expression in human DCs has a key role in instructing adaptive immunity and identified MERTK as a potent suppressor of T-cell response. Therefore targeting MERTK may provide an interesting approach to effectively increase or suppress tolerance for the purpose of immunotherapy., Esta tesis doctoral estudia el proceso de generación de células dendríticas tolerogénicas en grado clínico, con el objetivo de establecer un protocolo destinado al tratamiento de la enfermedad de Crohn. El estudio realizado ha permitido la caracterización de dichas células y sus propiedades tolerogénicas, incluyendo la descripción novedosa de un marcador de células tolerogénicas y el estudio de sus propiedades funcionales relacionadas con la inducción de tolerancia.

La enfermedad de Crohn es una patología digestiva que cursa con inflamación en pacientes genéticamente susceptibles. Dada la relación entre la enfermedad de Crohn, microbiota y dieta, se ha revisado el rol de los alimentos funcionales para modificar la flora microbiana y/o promover la síntesis de citocinas antiinflamatorias y disminuir la inflamación, postulando que una dieta adecuada podría ser utilizada para beneficiar el estado de salud de esta población. La malaltia de Crohn és una patologia digestiva que cursa amb inflamació en pacients genèticament susceptibles. Donada la relació entre la malaltia de Crohn, microbiota i dieta, s'ha revisat el rol dels aliments funcionals per modificar la flora microbiana i/o promoure la síntesi de citocines antiinflamatòries i disminuir la inflamació, postulant que una dieta adequada podria ser utilitzada per beneficiar l'estat de salut d'aquesta població.

Background: There is little information about the effect of infliximab on the clinical course of liver disease in Crohn’s disease patients with concomitant hepatitis B virus (HBV) infection. Theoretically, immunosuppression induced by infliximab will facilitate viral replication which could be followed by a flare or exacerbation of disease when therapy is discontinued. There are no specific recommendations on surveillance and treatment of HBV before infliximab infusion. Two cases of severe hepatic failure related to infliximab infusions have been described in patients with rheumatic diseases. Patients and methods: Hepatitis markers (C and B) and liver function tests were prospectively determined to 80 Crohn’s disease patients requiring infliximab infusion in three hospitals in Spain. Results: Three Crohn’s disease patients with chronic HBV infection were identified. Two of the three patients with chronic HBV infection suffered severe reactivation of chronic hepatitis B after withdrawal of infliximab therapy and one died. A third patient, who was treated with lamivudine at the time of infliximab therapy, had no clinical or biochemical worsening of liver disease during or after therapy. From the remaining 80 patients, six received the hepatitis B vaccine. Three patients had antibodies to both hepatitis B surface antigen (anti-HBs) and hepatitis B core protein (anti-HBc) with normal aminotransferase levels, and one patient had positive anti-hepatitis C virus (HCV) antibodies, negative HCV RNA, and normal aminotransferase levels. Except for the patients with chronic HBV infection, no significant changes in hepatic function were detected. Conclusions: Patients with Crohn’s disease who are candidates for infliximab therapy should be tested for hepatitis B serological markers before treatment and considered for prophylaxis of reactivation using antiviral therapy if positive.

Faecalibacterium prausnitzii és un del bacteris anaeròbis més abundants entre les espècies comensals del tracte intestinal humà sa. Aquesta espècie és una de les principals productores de butirat a l'intestí (que és la principal font d’energia per als colonòcits), però també s'ha suggerit que pot produir compostos antiinflamatoris i intervenir en la regulació de vàries rutes metabòliques de l’hoste. F. prausnitzii és un bacteri difícil de cultivar, ja que presenta una elevada sensibilitat a l'oxigen i presenta uns requeriments nutricionals molt exigents, el que ha compromès considerablement el nombre d’estudis basats en aïllats d’aquesta espècie. No obstant això, en els darrers anys l’interès en aquest bacteri està creixent ja que s’ha evidenciat que les poblacions de F. prausnitzii són variables en diferents grups d'edat i que es veuen reduïdes en certs trastorns intestinals com ara la malaltia inflamatòria intestinal i el càncer colorectal. L’objectiu d'aquest treball ha estat aprofundir en el rol que desenvolupa F. prausnitzii com un dels principals bacteris comensals del tracte intestinal humà. En primer lloc, s’ha dissenyat, optimitzat i validat un nou mètode molecular per determinar l’abundància d’aquesta espècie en mostres del tracte gastrointesinal, i s’ha demostrat la seva possible aplicació per ajudar al diagnòstic de la malaltia de Crohn. En segon lloc, s’ha dut a terme un estudi de les característiques filogenètiques i fenotípiques dels aïllats de F. Prausnitzii disponibles en l'actualitat a fi de coneixre’n millor la diversitat genètica i fenotípica i dilucidar quins factors són crucials en comprometre la població d’aquest bacteri en un intestí malalt. L’anàlisi de les soques ha revelat que F. prausnitzii inclou Principalment dos filogrups, nutricionalment versàtils i molt sensibles a canvis en les condicions ecològiques que pot patir l’intestí de l’hoste sota certes malalties intestinals. En conclusió, els resultat obtinguts en aquest estudi mostren que F. prausnitzii és una espècie ben establerta al còlon sa, amb una elvada versatilitat metabòlica ja que és capaç d’ interactuar amb carbohidrats de diferent estructura i complexitat. S’ha corroborat que aquest microorganisme seria un bon indicador de salut intestinal ja que la seva abundància es veu significativament reduida en pacients amb malaltia de Crohn. Aquests resultats concorden amb els obtinguts per proves fisiològiques que mostren una elevada sensibilitat de l’espècie a determinades condicions relacionades amb malalties intestinals. Estudis futurs s’orientaran a comprendre millor quins factros derrivats de la interacció amb l’hoste també determinen la persistència d’aquesta espècie en un intestí sa o malalt. Faecalibacterium prausnitzii is one of the most abundant anaerobic commensal bacteria in the healthy human large intestine. F. prausnitzii is one of the major butyrate producers in the gut, but it has also been suggested that it can produce other anti-inflammatory compounds and regulate many host metabolic pathways. F. prausnitzii has been shown to be a fastidious bacterium given its high oxygen sensitivity and nutritional requirements, so little attention has been paid to this species since its firstly isolated. However, there is an increasing interest concerning this species, since it has been recently reported that F. prausnitzii populations are variable in different age groups and also could be reduced in certain intestinal disorders such as Inflammatory Bowel Diseases and colorectal cancer. Therefore, the main aim of this research project is to deepen in this bacterium as one of the main gut human commensal bacterium. Firstly, we developed a new molecular method to monitor this species abundance in Inflammatory Bowel Diseases, further elucidating its applicability to assist the diagnostic of Crohn’s disease. Secondly, an study of the currently available isolates phylogenetical and phenotypical characteristics has been performed in order to better know F. prausnitzii genetic and phenotypic diversity and elucidate which factors are crucially compromising this commensal bacterium population in a diseased gut. Our data demonstrates that F. prausnitzii could mainly be divided in two phylogroups, being both nutritionally versatile and highly sensitive to changes in gut ecological conditions that may occur under certain intestinal disorders. In conclusion, the results derived from this work suggest that F. prausnitzii is a well established species in the colon, highly versatile due to its ability to grow on carbohydrates of different origin and structure. It has been corroborated that this species can be a good indicator of healthy intestinal microbial community given its significantly lower abundance in Crohn’s disease patients. These results are in agreement with the physiological data that revealed little tolerance by this bacterium to changes in the gut environmental conditions that frequently happen under intestinal diseases. Future studies will be addressed to explore which host derived factors may be also compromising F. prausnitzii persistence in a healthy or diseased intestine.

The developments in enteral feeding for Crohn's disease in the past decade are critically reviewed. The advent of amino acid based chemically defined elemental diets signalled the end of 'total bowel rest' in the management of these patients. Subsequently, controlled clinical trials showed that elemental diets were as effective as corticosteroids in inducing clinical remission in patients with acute exacerbations of Crohn's disease. The later use of peptide based elemental diets, in Crohn's disease produced somewhat conflicting results. The initial uncontrolled studies suggest that polymeric whole protein diets might also be effective in the management of acute exacerbations of the disease, casting in turn doubts concerning the role of dietary antigens in the pathogenesis of Crohn's disease. Results of controlled studies comparing the use of elemental and polymeric diets as primary therapy in Crohn's disease have, however, also produced conflicting results. The results of one recent controlled trial in which the use of polymeric diet was compared with that of corticosteroids does, however, suggest that these diets may have a primary therapeutic effect in Crohn's disease. An analysis of the composition of some of the enteral diets used in different trials suggest that the effectiveness of enteral diets in treating active Crohn's disease might relate more to their fat than nitrogen composition. A hypothesis is proposed that the effectiveness of enteral nutrition in the primary therapy of acute exacerbations of Crohn's disease occurs because the successful diets used contain insufficient precursors for arachidonate derived eicosanoid synthesis.

En el patró fibroestenosant de la malaltia de Crohn els fibroblasts intestinals augmenten en número contribuint al desenvolupament de la fibrosi. Un dels principals promotors de la proliferació d’aquestes cèl•lules és el bFGF. En el present estudi la fracció rica en tocotrienol ha demostrat tenir efectes antiproliferatius en fibroblasts intestinals humans independentment de la procedència dels fibroblasts. Els tocotrienols redueixen tant la proliferació basal com la induïda per bFGF en fibroblasts. L’apoptosi de les cèl•lules efectores en el desenvolupament de la fibrosi sembla ser el principal mecanisme de la seva resolució. Els tocotrienols instauraren un procés complert d’apoptosi en els fibroblasts. A diferència del que passa amb la majoria d’agents proapoptòtics, els tocotrienols provoquen l’activació tant de la via extrínseca com de la via intrínseca de l’apoptosi ja que activa les caspases 8 i 9. Sorprenentment, l’addició de ciclosporina A (CsA), un conegut inhibidor de la via intrínseca de l’apoptosi, bloqueja completament el procés d’apoptosi induït per FRT. Això demostra que tot i l’activació de la caspasa 8 i per tant, de la via extrínseca, en el tractament amb tocotrienols la predominant és la via intrínseca. L’autofàgia té un paper molt rellevant en l’aclariment de cossos apoptòtics. Els tocotrienols han demostrat eficàcia en la inducció d’autofàgia en fibroblasts, ja que provoca la maduració de la proteïna LC3 i l’aparició de vacuoles autofàgiques en el citoplasma d’aquestes cèl•lules. Un cop més la CsA reverteix aquest procés, i per tant inhibeix l’autofàgia, demostrant que aquest procés requereix la participació de la mitocòndria. Les patologies que cursen amb desenvolupament de fibrosi estan associades a alts nivells de TGF-β que resulta en el reclutament de fibroblasts al lloc de la lesió i a un increment en la producció de matriu extracel•lular. A nivell intracel•lular, la fosforilació d’Smad3 és el pas clau que regula les accions del TGF-β. Els tocotrienols han mostrat eficàcia en la disminució dels nivells intracel•lulars d’Smad3 fosforilada induïda per TGF-β. La fosforilació d’Smad3 té efectes oposats en la regulació de l’expressió gènica. Regula positivament l’expressió de TIMP-1, en canvi, regula negativament l’expressió de MMP-3. Tot i ser efectes oposats en quant a expressió gènica, aquests dos fenòmens afavoreixen l’acumulació de matriu extracel•lular. L’exposició a tocotrienols fa que es reverteixi aquest estat profibrogènic ja que indueix l’expressió de MMP-3 però no afecta als nivells de TIMP-1. La síntesi de MEC i especialment la síntesi de COL1, COL3 i COL5 està incrementada en la fibrosi intestinal, aquest fet està directament relacionat amb l’activitat de TGF-β en la zona afectada. Els tocotrienols interfereixen en la síntesi de col•lagen. A més, els tocotrienols disminueixen la fosforilació d’Smad3 induïda per TGF-β, un fet clau en la síntesi de matriu extracel•lular. Aquests resultats permeten hipotetitzar un potencial antifibrogènic dels tocotrienols. Per a confirmar aquest potencial “in vivo” ens calia disposar d’un model experimental de fibrosi intestinal. A diferència del que succeeix amb la colitis, en la que es disposa d’un gran nombre de models animals, hi ha pocs models experimentals específicament dissenyats per a reproduir la fibrosi intestinal. Aquest fet, ha limitat molt el desenvolupament de noves estratègies de tractament antifibrogènic en l’intestí. Mitjançant l’administració intracolònica repetida a dosis baixes de l’haptè TNBS vam poder establir fibrosi intestinal en la rata de manera rellevant i reproduïble. En aquest model de fibrosi intestinal, els animals que van rebre la dosi més alta de tocotrienols provada en aquest estudi van mostrar nivells disminuïts en paràmetres que mesuren la inflamació, això és, es va disminuir l’índex d’activitat de la malaltia i la pèrdua de pes causada pel TNBS així com també va reduir l’expressió de TNF-α., Excessive fibroblast expansion and extracellular matrix deposition are key events for the development of bowel stenosis in Crohn’s disease patients. Tocotrienols are vitamin E compounds with proven in vitro antifibrogenic effects on rat pancreatic fibroblasts. We aimed at investigating the effects of tocotrienols on human intestinal fibroblast proliferation, apoptosis, autophagy, and synthesis of ECM. Intestinal fibroblasts isolated from patients with Crohn’s disease were treated with tocotrienol-rich fraction from palm oil. Tocotrienols significantly reduced proliferation, enhanced cell death by promoting apoptosis and autophagy. Fibroblast apoptosis, but not autophagy, was prevented by the pan-caspase inhibitor zVAD-fmk, whereas both types of cell death were prevented when the mitochondrial permeability transition pore was blocked by cyclosporin A, demonstrating a key role of the mitochondria in these processes. TRF diminished procollagen type I and laminin γ production these cells. Transforming growth factor-β plays a key role in matrix deposition during fibrosis. Treatment of intestinal fibroblasts with tocotrienol rich fraction prevents Smad3 phosporylation induced by transforming growth factor-β and reduces collagen type 1 and 3 production by these cells. Besides, in a rat model of intestinal fibrosis, treatment with tocotrienols reduces diarrhea, rectal bleeding and weight loss, as well as levels of colonic tumor necrosis factor-α and vimentin expression demonstrating that this compound has anti-inflammatory effects in vivo.

[cat] La malaltia de Crohn és una malaltia inflamatòria intestinal de base immunitària. L’etiologia de la malaltia és desconeguda, encara que en general s’admet la següent definició: la malaltia és conseqüència d’una desregulació de la resposta immunitària en front als antígens comuns de la flora bacteriana intestinal en individus genèticament susceptibles. Un component important de la desregulació immunitària es la hiperactivació dels limfòcits T que es dóna en aquesta i altres malalties de tipus autoimmunitari, i en les que tradicionalment s’ha atribuït una major presència i producció de citocines per part de la població limfocitària Th1 en el teixit inflamat. Recentment, amb la descripció de la citocina IL-23 i la població Th17 se ha posat en dubte el paper principal de la població Th1 en les malalties inflamatòries de base immunitària. De fet, en algunes d’aquestes malalties s’ha descrit un augment de las cèl•lules Th17 així com de les citocines produïdes per aquesta població. L’objectiu d’aquesta tesi ha sigut caracteritzar el paper relatiu de les poblacions Th1 i Th17 en la mucosa intestinal inflamada i en la circulació perifèrica de pacients amb malaltia de Crohn activa o en remissió així com avaluar el paper i l’evolució d’aquestes poblacions limfocitàries en els estadis inicials (primers brots de la malaltia) i avançats de la malaltia. En aquest estudi observem que els períodes d’activitat inflamatòria en la malaltia de Crohn s’associen a una resposta sistèmica exacerbada de la població Th17, essent la producció de IL-17 en sobrenedant del cultiu de sang total, el percentatge de limfòcits CD4+IL-17+ i la producció de IL-17 per part d’aquestes cèl•lules més elevada que en els pacients amb malaltia inactiva i que en els controls sans. Paral•lelament hem descrit que la població Th1 circulant no presenta durant un brot d’activitat un augment tan generalitzat com la població Th17, sinó que només observem un augment en el percentatge de limfòcits CD4+IFN-γ+ circulants i en els dobles productors de IL-17 y IFN-γ. Els pacients que denominem debut (pateixen el primer brot de la malaltia) no presenten a nivell sistèmic un augment de la resposta Th17 ni Th1. A diferència del que observem en circulació perifèrica, en la mucosa intestinal inflamada trobem un augment dels trànscrits de les citocines característiques de la població Th17, tant en els pacients debut com en els que es troben en un estat més avançat de la malaltia. A més, en la mucosa inflamada d’ambdós grups de pacients trobem una major infiltració de cèl•lules IL-17+. A partir d’aquests resultats hipotetitzem un model per a la fisiopatologia de la malaltia de Crohn en el que la generació de limfòcits Th17 memòria podrien estar implicats en la cronicitat i recurrència de la malaltia. Així en les primeres fases de la malaltia només detectem un augment d’aquesta població en la mucosa intestinal, com seria d’esperar d’una resposta immunitària local. A conseqüència d’aquesta es generarà una població limfocitària de memòria immunitària que només detectem en circulació en aquells malalts que es troben ja en estadis més crònics de la malaltia. Amb aquesta hipòtesi podem explicar mitjançant mecanismes immunitaris diferents el fet que, en general, la malaltia de Crohn no es manifesta fins la segona o tercera dècada de vida d’un individu, mentre que un cop s’ha manifestat, la recurrència d’activitat inflamatòria és molt més freqüent (degut a la participació dels limfòcits memòria)., [eng]One component of the immune deregulation observed in Crohn’s disease is the massive infiltration of T lymphocytes in the inflamed tissue. Classically these hyperreactive lymphocytes have been attributed to the Th1 subpopulation. Recently the description of IL-23 cytokine and Th17 population has questioned the main role given to Th1 population. In this regard, an increase in the frequency of Th17 cells and in the production of their signature cytokines has been already described in some inflammatory diseases. In this study we have observed that active inflammation in Crohn’s disease associates to an increased systemic response of Th17 cells described as overproduction of IL-17 in supernatants of whole blood cultures, increased percentage of CD4+IL-17+ lymphocytes and increased production of IL-17 from these cells related to remission periods of disease or healthy controls. Early patients (patients who suffer their first flare of the disease) do not present a systemic increase of Th1 or Th17 cells despite suffering of active inflammation. Otherwise, in inflamed intestinal mucosa there is an increase in the expression of Th17 cytokines both in early as well as late chronic patients. Moreover we found a significant higher number of Th17 cells infiltrating the mucosa of both groups of patients. Taking these results into account we hypothesize a model for the physiopathology of Crohn’s disease in which the generation of memory Th17 lymphocytes could be involved in the chronicity and recurrence of the disease. Therefore, in early phases of disease we only detect an increase of this population in the intestinal mucosa, as we could expect from a local immune response. As a consequence of this activation there would be a generation of memory lymphocytes that we can detect in peripheral circulation only in that patients that have already suffered repeated flares of the disease. This hypothesis allows us to explain the different immune mechanisms that could be acting during the evolution of Crohn’s disease, as it is the first appearance of disease, generally occurring during the second or third decade of the individual life, and the subsequent appearance of recurrences that are much more frequent and life-long lasting.

Aim: To evaluate inflammatory activity in patients with Crohn's disease (CD) using technetium-99m-hexamethylpropyleneamine oxime (99mTc-HMPAO) granulocyte scintigraphy. Methods: Twenty patients (7 male and 13 female) with CD and five healthy volunteers were selected for 99mTc-HMPAO granulocyte scintigraphy. The Crohn's Disease Activity Index (CDAI), blood tests and C-reactive protein (CRP) of each patient were performed 7 d before the scintigraphic images. The leukocytes were labeled according to the International Society of Radiolabeled Blood Elements (ISORBE) consensus protocol and the scintigraphic images, including single photon emission computed tomography, were obtained 30 min and 2 h after injection of the radiolabeled leukocytes. Results: The labeling yield of the leukocytes with the lipophilic complex 99mTc-HMPAO was 55.0% +/- 10%. Six of the 20 patients (30%) presented congruent results for the three parameters investigated (CDAI, Scintigraphic Index and CRP). On the other hand, 14 patients (70%) did not show congruent results. There was no significant correlation between the indices analyzed according to the Spearman test (P > 0.05, n = 20). Conclusion: The results suggest that 99mTc-HMPAO-labeled leukocyte scintigraphy could be important for determining inflammatory activity in CD even in the absence of clinical symptoms.

Tanto en la E. de Crohn como en la CU, con una etiopatogenia aún desconocida, se postula la teoría de una disregulación inmunológica en individuos predispuestos genéticamente sobre los que actúan factores externos. Entre otros, la literatura recoge que fumar "protege" frente a la CU y "favorece" el desarrollo de E. de Crohn. Epidemiológicamente ambas presentan un pico de incidencia entre los 15 y los 30 años de edad, si bien la CU tiene una mayor afectación en hombres y la E. de Crohn en mujeres. En España las tasas de incidencia están aumentando en los últimos años, aunque lejos de las cifras de los países del norte de Europa. Fuera de los períodos de actividad los pacientes presentan una capacidad, funcionalidad y actividad laboral normales, superando en algunos estudios los datos laborales obtenidos por el grupo control. Las últimas innovaciones terapéuticas incluyen pautas con anticuerpos monoclonales quiméricos y se están haciendo estudios con trasplantes autólogos hematopoyéticos. En ASEPEYO, a lo largo del año 2006 ambas patologías han generado que el 0.012 % de sus afiliados a nivel nacional precisaran una incapacidad temporal (IT) por contingencia común. El 50% de los enfermos tenían menos de 35 años, el 62.9 % eran hombres y demográficamente la mitad de los casos se registraron entre Andalucía, Madrid y Cataluña. Casi el 85% de los casos duraron menos de 180 días y menos del 3% terminaron con la concesión de una Incapacidad Permanente (2% en grado de total y 0.86% en grado de absoluta)., ASEPEYO

Assessment of disease extension and activity is crucial to guide treatment in Crohn's disease. The objective of the current cross-sectional study was to determine the accuracy of MR for this assessment.50 patients with clinically active (n = 35) or inactive (n = 15) Crohn's disease underwent ileocolonoscopy (reference standard) and MR. T2-weighted and precontrast and postcontrast-enhanced T1-weighted sequences were acquired. Endoscopic activity was evaluated by CDEIS (Crohn's Disease Endoscopic Index of Severity); in addition endoscopic lesions were classified as absent, mild (inflammation without ulcers) or severe (presence of ulceration).The comparison of intestinal segments with absent, mild and severe inflammation demonstrated a progressive and significant (p0.001) increase in the following MR parameters: wall thickness, postcontrast wall signal intensity, relative contrast enhancement, presence of oedema, ulcers, pseudopolyps and lymph node enlargement. Independent predictors for CDEIS in a segment were wall thickness (p = 0.007), relative contrast enhancement (p = 0.01), presence of oedema (p = 0.02) and presence of ulcers at MR (p = 0.003). There was a significant correlation (r = 0.82, p0.001) between the CDEIS of the segment and the MR index calculated according to the logistic regression analysis coefficients. The MR index had a high accuracy for the detection of disease activity (area under the receiver operating characteristic (ROC) curve 0.891, sensitivity 0.81, specificity 0.89) and for the detection of ulcerative lesions (area under the ROC curve 0.978, sensitivity 0.95, specificity 0.91) in the colon and terminal ileum.The accuracy of MR for detecting disease activity and assessing severity brings about the possibility of using MR as an alternative to endoscopy in the evaluation of ileocolonic Crohn's disease.

La malaltia de Crohn és una malaltia inflamatòria intestinal crònica d'etiologia encara desconeguda. Actualment es pensa que hi participen factors genètics i immunològics que confereixen una susceptibilitat a l'hoste, i factors externs o ambientals, com serien els microorganismes i/o l'estil de vida. L'objectiu principal d'aquest treball ha estat descriure les poblacions bacterianes associades especialment als malalts de Crohn, amb la intenció d'identificar possibles agents etiològics. Els resultats d'aquest treball coincideixen amb investigacions prèvies que descriuen l'alteració bacteriana present en els malalts de Crohn (disbiosi) i recolzen la hipòtesi que implica el recentment descrit patovar "Adherent- Invasive Escherichia coli" (AIEC) en l'etiologia d'aquesta malaltia inflamatòria intestinal. A més, contribuïm a la descripció de les poblacions d'E. coli associades a la mucosa intestinal aportant dades sobre aspectes ecològics i patogènics. Finalment, descrivim nous aspectes fenotípics d'AIEC que podrien estar relacionats amb la seva patogènia, com seria la capacitat de formar biofilms., Crohn's disease is a chronic inflammatory bowel disorder of unknown aetiology. Genetic and immunologic features that confer susceptibility on the host, together with external or environmental factors such as microorganisms and lifestyle, are thought to be involved. The main purpose of this work was to describe the bacterial populations particularly related with Crohn's disease patients in order to identify putative etiologic agents. The results are in agreement with previous research on the entire microbial community associated with Crohn's disease, providing evidence of a situation of dysbiosis, and further support the hypothesis of a putative implication of the recently described pathovar Adherent-Invasive Escherichia coli (AIEC). In addition, this work contributes to the understanding of mucosa-associated E. coli populations by providing new data about their ecological parameters and pathogenic features. Finally, we have also contributed to a better description of the AIEC pathovar by contrasting it with close pathogenic E. coli strains and finding new pathogenic features such as biofilm formation.

La presencia de microorganismos patógenos en alimentos es uno de los problemas esenciales en salud pública, y las enfermedades producidas por los mismos es una de las causas más importantes de enfermedad. Por tanto, la aplicación de controles microbiológicos dentro de los programas de aseguramiento de la calidad es una premisa para minimizar el riesgo de infección de los consumidores. Los métodos microbiológicos clásicos requieren, en general, el uso de pre-enriquecimientos no-selectivos,enriquecimientos selectivos, aislamiento en medios selectivos y la confirmación posterior usando pruebas basadas en la morfología, bioquímica y serología propias de cada uno de los microorganismos objeto de estudio. Por lo tanto, estos métodos son laboriosos, requieren un largo proceso para obtener resultados definitivos y, además, no siempre pueden realizarse. Para solucionar estos inconvenientes se han desarrollado diversas metodologías alternativas para la detección identificación y cuantificación de microorganismos patógenos de origen alimentario, entre las que destacan los métodosinmunológicos y moleculares. En esta última categoría, la técnica basada en la reacción en cadena de la polimerasa (PCR) se ha convertido en la técnica diagnóstica más popular en microbiología, y recientemente, la introducción de una mejora de ésta, la PCR a tiempo real, ha producido una segunda revolución en la metodología diagnóstica molecular, como pude observarse por el número creciente de publicaciones científicas y la aparición continua de nuevos kits comerciales. La PCR a tiempo real es unatécnica altamente sensible -detección de hasta una molécula- que permite la cuantificación exacta de secuencias de ADN específicas de microorganismos patógenos de origen alimentario. Además, otras ventajas que favorecen su implantación potencial en laboratorios de análisis de alimentos son su rapidez, sencillez y el formato en tubo cerrado que puede evitar contaminaciones post-PCR y favorece la automatización y un alto rendimiento. En este trabajo se han desarrollado técnicas moleculares (PCR y NASBA) sensibles y fiables para la detección, identificación y cuantificación de bacterias patogénicas de origen alimentario (Listeria spp., Mycobacterium avium subsp. paratuberculosis y Salmonella spp.). En concreto, se han diseñado y optimizado métodos basados en la técnica de PCR a tiempo real para cada uno de estos agentes: L. monocytogenes, L. innocua, Listeria spp. M. avium subsp. paratuberculosis, y también se ha optimizado yevaluado en diferentes centros un método previamente desarrollado para Salmonella spp. Además, se ha diseñado y optimizado un método basado en la técnica NASBA para la detección específica de M. avium subsp. paratuberculosis. También se evaluó la aplicación potencial de la técnica NASBA para la detección específica de formas viables de este microorganismo. Todos los métodos presentaron una especificidad del 100 % con una sensibilidad adecuada para su aplicación potencial a muestras reales de alimentos. Además, se han desarrollado y evaluado procedimientos de preparación de las muestras en productos cárnicos, productos pesqueros, leche y agua. De esta manera se han desarrollado métodos basados en la PCR a tiempo real totalmente específicos y altamente sensibles para la determinación cuantitativa de L. monocytogenes en productoscárnicos y en salmón y productos derivados como el salmón ahumado y de M. avium subsp. paratuberculosis en muestras de agua y leche. Además este último método ha sido también aplicado para evaluar la presencia de este microorganismo en el intestino de pacientes con la enfermedad de Crohn's, a partir de biopsias obtenidas de colonoscopia de voluntarios afectados.En conclusión, este estudio presenta ensayos moleculares selectivos y sensibles para la detección de patógenos en alimentos (Listeria spp., Mycobacterium avium subsp. paratuberculosis) y para una rápida e inambigua identificación de Salmonella spp. La exactitud relativa de los ensayos ha sido excelente, si se comparan con los métodos microbiológicos de referencia y pueden serusados para la cuantificación de tanto ADN genómico como de suspensiones celulares. Por otro lado, la combinación con tratamientos de preamplificación ha resultado ser de gran eficiencia para el análisis de las bacterias objeto de estudio. Por tanto, pueden constituir una estrategia útil para la detección rápida y sensible de patógenos en alimentos y deberían ser una herramienta adicional al rango de herramientas diagnósticas disponibles para el estudio de patógenos de origen alimentario., The presence of pathogens in foods is among the most serious public health concerns, and the diseases produced by them are a major cause of morbidity. Consequently, the application of microbiological control within the quality assessment programs in the food industry is a premise to minimize the risk of infection for the consumer. Classical microbiological methods involve, in general, the use of a non-selective pre-enrichment, selective enrichment, isolation on selective media, and subsequent confirmation using morphological, biochemical and/or serological tests. Thus, they are laborious, time consuming and not always reliable (e.g. in viable but non-culturable VBNC forms). A number of alternative, rapid and sensitive methods for the detection, identification and quantification of foodborne pathogens have been developed to overcome these drawbacks. PCR has become the most popular microbiological diagnostic method, and recently, the introduction of a development of this technique, RTi-PCR, has produced a second revolution in the molecular diagnostic methodology in microbiology. RTi-PCR is highly sensitive and specific. Moreover, it allows accurate quantification of the bacterial target DNA. Main advantages of RTi-PCR for its application in diagnostic laboratories include quickness, simplicity, the closed-tube format that avoids risks of carryover contaminations and the possibility of high throughput and automation.In this work, specific, sensitive and reliable analytical methods based on molecular techniques (PCR and NASBA) were developed for the detection, identification and quantification of foodborne pathogens (Listeria spp., Mycobacterium avium subsp. paratuberculosis and Salmonella spp.). Real-time PCR based methods were designed and optimised for each one of these target bacteria: L. monocytogenes, L. innocua, Listeria spp. M. avium subsp. paratuberculosis, and also a real-time PCR basedmethod previously described for Salmonella spp. was optimised and multicenter evaluated. In addition, an NASBA-based method was designed and optimised for the specific detection of M. avium subsp. paratuberculosis. The potential application of the NASBA technique for specific detection of viable M. avium subsp. paratuberculosis cells was also evaluated.All the amplification-based methods were 100 % specific and the sensitivity achieved proved to be fully suitable for further application in real food samples. Furthermore, specific pre-amplification procedures were developed and evaluated on meatproducts, seafood products, milk and water samples. Thus, fully specific and highly sensitive real-time PCR-based methods were developed for quantitative detection of L. monocytogenes on meat and meat products and on salmon and cold smoked salmon products; and for quantitative detection of M. avium subsp. paratuberculosis on water and milk samples. The M. avium subsp. paratuberculosis-specific real-time PCR-based method was also applied to evaluate the presence of this bacterium in the bowelof Crohn's disease patients using colonic biopsy specimens form affected and unaffected volunteers. In addition, fully specific and highly sensitive real-time NASBA-based methods were developed for detection of M. avium subsp. paratuberculosis on water and milk samples.In conclusion, this study reports selective and sensitive amplification-based assays for the quantitative detection of foodborne pathogens (Listeria spp., Mycobacterium avium subsp. paratuberculosis and) and for a quick and unambiguously identification of Salmonella spp. The assays had an excellent relative accuracy compared to microbiological reference methods and can be used for quantification of genomic DNA and also cell suspensions. Besides, in combination with sample pre-amplification treatments,they work with high efficiency for the quantitative analysis of the target bacteria. Thus, they could be a useful strategy for a quick and sensitive detection of foodborne pathogens in food products and which should be a useful addition to the range of diagnostic tools available for the study of these pathogens.

El tacrólimus (FK506) es un fármaco inmunomodulador de uso extendido en el ámbito del trasplante de órganos pero del que existe escasa experiencia en el tratamiento de la enfermedad inflamatoria intestinal (EII). Objetivo: analizar la eficacia del tacrólimus en determinadas presentaciones clínicas de la EII caracterizadas por su carácter multirrecidivante. Pacientes y métodos: los criterios de inclusión fueron: enfermedad de Crohn perianal (ECP) y rectal; reservoritis y cuffitis con afectación severa de la función del reservorio ileoanal (RIA). Todas ellas refractarias al tratamiento convencional. Criterios de valoración clínica: clasificación de Hughes (ECP), índice funcional de Oresland (IO), endoscopia-biopsia y calidad de vida (CV) mediante la versión española del IBDQ. El tacrólimus se admistró por vía oral a una dosis de 0,1 mg/kg/día (niveles: 5-15 μg/L). Las respuestas se consideraron completas (RC), parciales (RP) o ausencia de las mismas (FR). Resultados: diecinueve pacientes entraron en el estudio. La duración media del tratamiento fue de 9,6 ± 6,3 meses. En la ECP hubo un 66% de RC y 33% de RP con desaparición de inflamación, estenosis y úlceras. En pacientes con reservoritis y cuffitis se registró un 77% de RC y RP. Tanto el IO como la CV experimentaron una mejoría significativa al finalizar el tratamiento (p

El tacrólimus (FK506) es un fármaco inmunomodulador de uso extendido en el ámbito del trasplante de órganos pero del que existe escasa experiencia en el tratamiento de la enfermedad inflamatoria intestinal (EII). Objetivo: analizar la eficacia del tacrólimus en determinadas presentaciones clínicas de la EII caracterizadas por su carácter multirrecidivante. Pacientes y métodos: los criterios de inclusión fueron: enfermedad de Crohn perianal (ECP) y rectal; reservoritis y cuffitis con afectación severa de la función del reservorio ileoanal (RIA). Todas ellas refractarias al tratamiento convencional. Criterios de valoración clínica: clasificación de Hughes (ECP), índice funcional de Oresland (IO), endoscopia-biopsia y calidad de vida (CV) mediante la versión española del IBDQ. El tacrólimus se admistró por vía oral a una dosis de 0,1 mg/kg/día (niveles: 5-15 μg/L). Las respuestas se consideraron completas (RC), parciales (RP) o ausencia de las mismas (FR). Resultados: diecinueve pacientes entraron en el estudio. La duración media del tratamiento fue de 9,6 ± 6,3 meses. En la ECP hubo un 66% de RC y 33% de RP con desaparición de inflamación, estenosis y úlceras. En pacientes con reservoritis y cuffitis se registró un 77% de RC y RP. Tanto el IO como la CV experimentaron una mejoría significativa al finalizar el tratamiento (p

La Enfermedad Inflamatoria Intestinal (EII) incluye la enfermedad de Crohn y la colitis ulcerosa. Numerosos estudios relacionan dichas afectaciones con la manifestación de determinadas lesiones orales. Respecto a la enfermedad periodontal algunos autores la correlacionan con la EII tanto en su prevalencia como en su grado de actividad. Se ha apuntado la alteración de los PMN como posible factor común en la patogénesis de ambas entidades. El propósito de nuestro artículo es revisar las manifestaciones orales que presentan los pacientes afectos de una EII, así como dilucidar su implicación con la enfermedad periodontal. Además se repasa el manejo del paciente odontológico con EII sometido a corticoterapia.

Thirty two patients with active Crohn's disease were included in a controlled randomised trial to determine the efficacy and safety of polymeric enteral nutrition compared with steroids, to achieve and maintain clinical remission. The polymeric diet was administered through a fine bore nasogastric tube by continuous, pump assisted infusion (2800 (SEM 120) kcal/day). The steroid group received 1 mg/kg/day of prednisone. Both treatments were effective in inducing clinical remission: 15 of the 17 patients given steroids and 12 of the 15 patients assigned to the polymeric diet went into clinical remission (defined by a Van Hees index < 120) within four weeks of treatment. The percentage reduction of the Van Hees index was 34.8 (4.9)% for steroids and 32.3 (5)% for enteral nutrition (mean difference 2.5%; 95% CI--11.8% to +16.8%). Mean time elapsed to achieve remission was similar in both groups (2.0 (1) v 2.4 (1.2) weeks). Tolerance of the enteral diet was excellent. Four patients in the steroid group had mild complications attributable to this treatment. Ten patients (66.6%) in the steroid group and five (41.6%) in the enteral nutrition group relapsed within a year of discharge, but no differences were found in the cumulative probability of relapse during the follow up period. These results suggest that polymeric enteral nutrition is as safe and effective as steroids in inducing short term remission in active Crohn's disease.

Background and Aims: Despite the negative results of blocking IL-17 in Crohn's disease (CD) patients, selective modulation of Th17-dependent responses warrants further study. Inhibition of retinoic acid-related orphan receptor gamma (RORγt), the master regulator of the Th17 signature, is currently being explored in inflammatory diseases. Our aim was to determine the effect of a novel oral RORγt antagonist (BI119) in human CD and on an experimental model of intestinal inflammation. Methods: 51 CD patients and 11 healthy subjects were included. The effects of BI119 were tested on microbial-stimulated peripheral blood mononuclear cells (PBMCs), intestinal crypts and biopsies from CD patients. The ability of BI119 to prevent colitis in vivo was assessed in the CD4+CD45RBhigh T cell transfer model. Results: In bacterial antigen-stimulated PBMCs from CD patients, BI119 inhibits Th17-related genes and proteins, while upregulating Treg and preserving Th1 and Th2 signatures. Intestinal crypts cultured with supernatants from BI119-treated commensal-specific CD4+ T cells showed decreased expression of CXCL1, CXCL8 and CCL20. BI119 significantly reduced IL17 and IL26 transcription in colonic and ileal CD biopsies and did not affect IL22. BI119 has a more profound effect in ileal CD with additional significant downregulation of IL23R, CSF2, CXCL1, CXCL8, and S100A8, and upregulation of DEFA5. BI119 significantly prevented development of clinical, macroscopic and molecular markers of colitis in the T-cell transfer model. Conclusions: BI119 modulated CD-relevant Th17 signatures, including downregulation of IL23R while preserving mucosa-associated IL-22 responses, and abrogated experimental colitis. Our results provide support to the use of RORγt antagonists as a novel therapy to CD treatment.

Background Crohn’s disease (CD) is an inflammatory bowel disease caused by genetic and environmental factors. More than 160 susceptibility loci have been identified for IBD, yet a large part of the genetic variance remains unexplained. Recent studies have demonstrated genetic differences between monozygotic twins, who were long thought to be genetically completely identical. Results We aimed to test if somatic mutations play a role in CD etiology by sequencing the genomes and exomes of directly affected tissue from the bowel and blood samples of one and the blood-derived exomes of two further monozygotic discordant twin pairs. Our goal was the identification of mutations present only in the affected twins, pointing to novel candidates for CD susceptibility loci. We present a thorough genetic characterization of the sequenced individuals but detected no consistent differences within the twin pairs. An estimate of the CD susceptibility based on known CD loci however hinted at a higher mutational load in all three twin pairs compared to 1,920 healthy individuals. Conclusion Somatic mosaicism does not seem to play a role in the discordance of monozygotic CD twins. Our study constitutes the first to perform whole genome sequencing for CD twins and therefore provides a valuable reference dataset for future studies. We present an example framework for mosaicism detection and point to the challenges in these types of analyses. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-564) contains supplementary material, which is available to authorized users.

Dendritic cells have been investigated in clinical trials, predominantly with the aim of stimulating immune responses against tumours or infectious diseases. Thus far, however, no clinical studies have taken advantage of their specific immunosuppressive potential. Tolerogenic DCs may represent a new therapeutic strategy for human immune-based diseases, such as Crohn’s disease, where the perturbations of the finely tuned balance between the immune system and the microflora result in disease. In the present report, we describe the generation of tolerogenic DCs from healthy donors and Crohn’s disease patients using clinical-grade reagents in combination with dexamethasone as immunosuppressive agent and characterize their response to maturation stimuli. Interestingly, we found out that dexamethasone-conditioned DCs keep their tolerogenic properties to Gram-negative bacteria. Other findings included in this study demonstrate that the combination of dexamethasone with a specific cytokine cocktail yielded clinical-grade DCs with the following characteristics: a semi-mature phenotype, a pronounced shift towards anti-inflammatory versus inflammatory cytokine production and low T-cell stimulatory properties. Importantly, in regard to their clinical application, the tolerogenic phenotype of DCs remained stable after the elimination of dexamethasone and after a second stimulation with LPS or bacteria. All these properties make this cell product suitable to be tested in clinical trials of inflammatory conditions including Crohn’s disease.