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La pandemia por COVID-19 ha supuesto un reto para los países y sus profesionales sanitarios. La entrada viral en el hospedador a través del receptor ACE-2 y una activación excesiva del sistema inmunológico son claves para comprender tanto la incidencia como la gravedad de la enfermedad. La enfermedad inflamatoria intestinal (EII) representa una condición especial asociada con una respuesta descontrolada del sistema inmunológico a agentes externos. Los tratamientos para la EII se han asociado con un mayor riesgo de infecciones bacterianas y virales. Esto ha planteado la cuestión de una posible mayor incidencia y gravedad de la infección por COVID-19 en pacientes con EII. A lo largo de este año se han publicado varios artículos que tratan de responder esa cuestión. La vacunación contra la COVID-19 ofrece una gran promesa para controlar la infección en pacientes con EII. Según la evidencia actual, los pacientes con EII no tienen mayor incidencia de COVID-19 ni peor evolución de la enfermedad en comparación con la población general. La edad avanzada y la presencia de un mayor número de comorbilidades se han asociado con peores resultados. Los corticosteroides están asociados con un mayor riesgo de infección por COVID-19, una mayor tasa de hospitalizaciones y un mayor riesgo de COVID-19 grave. La mesalazina/sulfasalazina y las tiopurinas presentan un posible aumento del riesgo de COVID-19 grave, aunque se requieren más estudios para demostrar esta asociación. Dentro de los fármacos biológicos, los anti-TNF pueden tener un posible efecto protector. Los anti-IL-12/23, anti-integrinas y tofacitinib presentan resultados comparables con anti-TNF. Se recomienda mantener el tratamiento con agentes biológicos. En base a la eficacia, las recomendaciones de los expertos y la ausencia de otra evidencia, se recomienda la vacunación de pacientes con EII.

Purpose: This study was performed to evaluate the long-term evolution of continence and patient’s quality of life after surgical treatment for obstetric fecal incontinence.Methods: A prospective longitudinal study was conducted including consecutive patients who underwent sphincteroplasty for severe obstetric fecal incontinence. The first phase analyzed changes in continence and impact on quality of life. The second phase studied the long-term evolution reevaluating the same group of patients 6 years later. Degree of fecal incontinence was calculated using the Cleveland Clinic Score (CCS). Quality of life assessment was carried out with the Fecal Incontinence Quality of Life scale.Results: Thirty-five patients with median age of 55 years (range, 28 to 73 years) completed the study. Phase 1 results: after a postoperative follow-up of 30 months (4 to 132 months), CCS had improved significantly from a preoperative of 15.7 ± 3.1 to 6.1 ± 5.0 (P < 0.001). Phase 2 results: median follow-up in phase 2 was 110 months (76 to 204 months). The CCS lowered to 8.4 ± 4.9 (P = 0.04). There were no significant differences between phases 1 and 2 in terms of quality of life; lifestyle (3.47 ± 0.75 vs. 3.16 ±1.04), coping/behavior (3.13 ±0.83 vs. 2.80 ±1.09), depression/self-perception (3.65 ±0.80 vs. 3.32 ± 0.98), and embarrassment (3.32 ± 0.90 vs. 3.12 ± 1.00).Conclusion: Sphincteroplasty offers good short-medium term outcomes in continence and quality of life for obstetric fecal incontinence treatment. Functional clinical results deteriorate over time but did not impact on patients’ quality of life.

The identification of LSN3318839, a positive allosteric modulator of the glucagon-like peptide-1 receptor (GLP-1R), is described. LSN3318839 increases the potency and efficacy of the weak metabolite GLP-1(9-36)NH2 to become a full agonist at the GLP-1R and modestly potentiates the activity of the highly potent full-length ligand, GLP-1(7-36)NH2. LSN3318839 preferentially enhances G protein-coupled signaling by the GLP-1R over β-arrestin recruitment. Ex vivo experiments show that the combination of GLP-1(9-36)NH2 and LSN3318839 produces glucose-dependent insulin secretion similar to that of GLP-1(7-36)NH2. Under nutrient-stimulated conditions that release GLP-1, LSN3318839 demonstrates robust glucose lowering in animal models alone or in treatment combination with sitagliptin. From a therapeutic perspective, the biological properties of LSN3318839 support the concept that GLP-1R potentiation is sufficient for reducing hyperglycemia.

Measuring quality of care (QoC) from a patient’s perspective is becoming increasingly important in inflammatory bowel disease. The objective of this study was to determine whether patients’ evaluations of QoC correlate with better inflammatory bowel disease outcomes. A survey including patients’ characteristics, a decalogue of QoC indicators, and self-reported disease outcomes was completed by Spanish patients with inflammatory bowel disease. A QoC index (QoCI) was constructed with the sum of the “yes” answers in the decalogue. We evaluated the correlation of QoCI with outcomes. A sub-analysis comparing patients with high QoCI vs those with low QoCI was performed (QoCI = 10 or ≤ 7). Seven hundred and eighty-eight questionnaires were analyzed. Mean age of participants was 43.4 years (63% women). Mean QoCI was 8.1 (± 2.4). The QoCI correlated significantly with activity of the disease, number of flares, emergency/unscheduled visits, and disease control. Patients scoring in the first QoCI quartile reported a decreased rate of moderate/severe disease (34.8% vs 55.3%, p < 0.001), fewer numbers of flares (p < 0.001), and fewer emergency/unscheduled visits (p < 0.001) compared with those in the lower QoCI quartile. The high QoC group also reported better disease control. Patient-evaluated QoC correlates with better outcomes. Evaluation of QoC by patients may be useful to detect inadequate care and improve inflammatory bowel disease outcomes.

Patients with decompensated cirrhosis frequently require hospital admissions, which are associated with worse prognosis. The aim of this study was to analyze the effect of TIPS on the need for hospital care. Secondary objectives were to assess the clinical and biological impact of TIPS and to identify predictors of post-TIPS hospital care. An observational, retrospective study of patients with decompensated cirrhosis treated with TIPS from January 2008 until March 2019. Exclusion criteria were TIPS placed for non-cirrhotic portal hypertension (PH) and patients referred from another hospital without prior or subsequent follow-up at our Unit. Hospital care, PH-related complications, and laboratory data were compared before and after TIPS. The final cohort comprised 104 patients (72% male) with a mean age of 60 (± 10) years. Follow-up from first decompensation until TIPS and that from procedure to study completion were 7 (4.2–9.8) and 20 (4.6–35.4) months, respectively. TIPS was indicated mainly for refractory ascites (50%) and variceal bleeding (39%). Hemodynamic and clinical success rates were 97% and 92%, respectively. The number of emergency department visits and hospital admissions decreased after the procedure (p

Background Caustic ingestion is a potentially severe condition and early identification of poor outcome is essential to improve management; however, prediction based on endoscopy alone can overestimate severity. This study aimed to develop and validate a prognostic score. Methods A prospective cohort study was designed to include all consecutive patients aged > 15 years who presented with caustic ingestion between 1995 and 2017. Adverse outcome was defined by intensive care unit admission, urgent surgery, or death. The predictive value of clinical, analytical, and endoscopic variables was assessed in the first cohort (derivation cohort) and a prognostic score based on the resulting risk factors was developed by logistic regression. Internal validation (bootstrapping) was performed and then external validation was checked in an independent sample of patients (validation cohort). Results 469 cases of caustic ingestion were included, 265 in the derivation cohort and 204 in the validation cohort. Ingestion of acidic substances (odds ratio [OR] 3.13, 95 % confidence interval [CI] 2.33 – 4.21), neutrophil count (OR 1.05, 95 %CI 1.04 – 1.06), metabolic acidosis (bicarbonate value, OR 0.82, 95 %CI 0.78 – 0.85), and endoscopic injury (OR 3.81, 95 %CI 3.35 – 4.34) were independent risk factors for poor outcome. The prognostic score based on these variables provided better accuracy than endoscopy alone (P = 0.04), with high sensitivity, specificity, positive and negative predictive values (93.3 %, 92.7 %, 72.7 %, 98.5 %, respectively), and area under the curve (0.976, 95 %CI 0.973 – 0.979; P Conclusions This score allowed a reliable prognosis of caustic ingestion and was more accurate than endoscopy-based evaluation.

Recommendations are advice that is given and considered to be beneficial; however, they are still suggestions and are therefore open to different interpretations. In this sense, the final objective of the review has been to try to homogenize, with the evidence available, the approach to the diagnosis and medical/surgical treatment of one of the most complex manifestations of Crohn's disease, such as simple and complex perianal fistulas.

Resumen Las recomendaciones son consejos dados por considerarse beneficiosos y no dejan de ser sugerencias, abiertas por tanto a diferentes interpretaciones. En ese sentido, el objetivo final de la revision ha sido, con las evidencias disponibles, intentar homogeneizar al maximo la aproximacion al diagnostico y tratamiento medicoquirurgico de una de las manifestaciones mas complejas de la enfermedad de Crohn como son las fistulas perianales simples y complejas

We have developed a continuous flow method to enable rapid scaleup of an enantioenriched benzodioxan intermediate. We propose that the reaction proceeds through an intramolecular SNAr cyclization. ...

Resumen Aunque un elevado porcentaje de pacientes con colitis ulcerosa deberia recibir tratamiento topico por via rectal, los estudios de practica clinica han demostrado que este esta infrautilizado. El proposito de este articulo es el de responder a 10 preguntas concretas sobre que farmacos estan disponibles para uso topico, su forma de presentacion, formulacion y metodos de aplicacion, asi como cual de ellos es mas eficaz e idoneo en los distintos escenarios clinicos de la colitis ulcerosa. Asimismo, se evalua la posibilidad de combinar diferentes formulaciones y vias de administracion, y la utilidad en la fase de remision de la enfermedad. Por ultimo, se hacen una serie de recomendaciones para una mejor informacion de los pacientes acerca de una correcta aplicacion y administracion.

BACKGROUND AND AIMS: There is a need to evaluate the benefit-risk ratio of current therapies in inflammatory bowel disease (IBD) patients to provide the best quality of care. The primary objective of I-CARE (IBD Cancer and serious infections in Europe) was to assess prospectively safety concerns in IBD, with specific focus on the risk of cancer/lymphoma and serious infections in patients treated with anti-tumor necrosis factor and other biologic monotherapy as well as in combination with immunomodulators.METHODS: I-CARE was designed as a European prospective longitudinal observational multicenter cohort study to include patients with a diagnosis of Crohn's disease, ulcerative colitis, or IBD unclassified established at least 3 months prior to enrollment.RESULTS: A total of 10,206 patients were enrolled between March 2016 and April 2019, including 6169 (60.4%) patients with Crohn's disease, 3853 (37.8%) with ulcerative colitis, and 184 (1.8%) with a diagnosis of IBD unclassified. Thirty-two percent of patients were receiving azathioprine/thiopurines, 4.6% 6-mercaptopurine, and 3.2% methotrexate at study entry. At inclusion, 47.3% of patients were treated with an anti-tumor necrosis factor agent, 8.8% with vedolizumab, and 3.4% with ustekinumab. Roughly one-quarter of patients (26.8%) underwent prior IBD-related surgery. Sixty-six percent of patients had been previously treated with systemic steroids. Three percent of patients had a medical history of cancer prior to inclusion and 1.1% had a history of colonic, esophageal, or uterine cervix high-grade dysplasia.CONCLUSIONS: I-CARE is an ongoing investigator-initiated observational European prospective cohort study that will provide unique information on the long-term benefits and risks of biological therapies in IBD patients. (EudraCT, Number: 2014-004728-23; ClinicalTrials.gov, Number: NCT02377258).

Background Quality of care (QoC) is a highly important topic in inflammatory bowel disease (IBD). We recently elaborated a decalogue of QoC indicators (IQCARO-QoC) developed by IBD patients. The aim of the present study was to assess the factors associated with patients’ evaluation of QoC in Spain using the IQCARO-QoC Decalogue recently developed by IBD patients. Methods A survey including patients’ socio-demographic and clinical characteristics, and the IQCARO-QoC Decalogue, was completed by IBD patients. We described patients’ assessment of QoC across Spanish patients. A univariable and multivariable analysis was performed to explore the associations between patients’ characteristics and QoC. Results Questionnaires from 788 participant patients were analysed. Participants’ mean age was 43.4 years, 63% were females and 58% had Crohn’s disease. The mean QoC score was 8.1 (± 2.4 SD) points out of a maximum of 10. Items with the lowest score were related to the provision of information and the implication of the medical team throughout the entire patient care. Factors associated with better QoC scores included: being employed better disease control, fewer numbers of unscheduled visits, and being followed by a gastroenterologist specialized in IBD. Conclusions Spanish patients’ reported QoC seems to be globally good although there is room for improvement, especially in providing adequate information to patients. Care provided by specialized IBD gastroenterologists seems to be related with higher QoC scores.

Background Quality improvement is a major topic in inflammatory bowel disease (IBD) care, and measuring quality of care (QoC) is necessary for QoC improvement. Most QoC projects or consensus statements are designed from the health care professional point of view. Having QoC indicators designed for and fully evaluable by patients may provide a key tool for external evaluation of QoC improvement measures. The aim of the IQCARO project was to identify indicators to measure QoC from the IBD patient’s point of view. Methods An extensive review of the literature to identify indicators of QoC was performed; first the identified indicators were reviewed by a steering committee including patients, nurses, IBD specialists, and methodologists. Then 2 focus groups of IBD patients analyzed the QoC indicators to determine whether they could be understood and evaluated by patients. The final QoC indicators were selected by a group of IBD patients using a Delphi consensus methodology. Results An initial list of 54 QoC indicators was selected by the steering committee. The QoC indicators were evaluated by 16 patients who participated in 2 focus groups. They identified 21 indicators that fulfilled the understandability and evaluability requirements. The 10 most relevant QoC indicators were selected by 26 patients with IBD using a Delphi consensus. The selected items covered important aspects of QoC, including professionalism, patients’ autonomy, information, accessibility, and continuity of care. Conclusions The present Delphi consensus identified QoC indicators that are useful for developing and measuring improvement strategies in the management of IBD.

BACKGROUND: Knowing patients' ulcerative colitis history is essential to selecting the appropriate therapy according to risk stratification. OBJECTIVE: To evaluate and identify predictive factors of non-response to aminosalicylates judged as the need for a step-up approach over time. METHODS: A case-control study of ulcerative colitis patients treated with aminosalicylates after the diagnosis of disease flare included in the ENEIDA single-centre registry from 1997 to 2017. Long-term treatment maintenance with aminosalicylates and higher therapeutic requirements were recorded. The cumulative incidence of treatment escalation was estimated using Kaplan-Meier curves and compared by the log-rank test. Cox regression analysis was performed to identify predictive factors of treatment with immunomodulators, biological agents or surgery. RESULTS: A total of 457 patients were included, of whom 28% (n = 126) were non-responders to aminosalicylates. The cumulative probability for a step-up approach within 20 years of follow up was 35%, mainly due to steroid-dependent colitis. Risk factors for treatment escalation were age ≤27 years (hazard ratio 2.31, 95% confidence interval 1.36–3.92), extensive colitis (hazard ratio 1.65, 95% confidence interval 1.04–2.60), Mayo endoscopic subscore ≥2 (hazard ratio 1.45, 95% confidence interval 1.02–2.06) and extraintestinal manifestations (hazard ratio 2.04, 95% confidence interval 1.03–4.05). CONCLUSIONS: Aminosalicylates represent an effective maintenance therapy. Younger age, extensive colitis, endoscopic disease severity and extraintestinal manifestations are risk factors for higher therapeutic requirements.

Malnutrition is frequent in patients with cirrhosis and has been associated with poor prognosis. The Model for End-stage Liver Disease (MELD) score was created to predict survival after Transjugular Intrahepatic Porto-systemic Shunt (TIPS) but lacks a nutritional parameter.To evaluate the prognostic value of serum cholesterol in patients with cirrhosis undergoing TIPS and to develop a prognostic score to predict survival.An explorative cross-sectional study was conducted of cirrhotic patients undergoing TIPS from 2008 until 2019. Exclusion criteria were liver transplantation or hepatocellular carcinoma before TIPS. Risk analysis was used to compare survival according to clinical and analytical data. The diagnostic performance of serum cholesterol added to MELD was evaluated and confirmed in an external validation cohort.The final cohort of 100 patients had a mean MELD score of 14±5 and cholesterol of 122±51 mg/dL. MELD (p 0,05) and both cholesterol (p 0,05) and low-density lipoprotein levels (LDL-C) (p 0,05) were independent predictors of post-TIPS transplant-free survival with an optimal cut-off of 106 mg/dL for serum cholesterol. The combined MELD-cholesterol risk score improved diagnostic accuracy of each parameter separately, and this was confirmed in the external cohort.Serum cholesterol and LDL-C are independent predictors of transplant-free survival in cirrhotic patients undergoing TIPS. The MELD-cholesterol score slightly improved prognostic accuracy.As an objective and easily measured indicator of both nutritional status and hepatic function, serum cholesterol could be useful to predict transplant-free survival in patients with cirrhosis undergoing TIPS. It can enable health care providers to identify high-risk patients and to optimize nutritional status before TIPS.

Aminosalicylates (5-ASA) represent the first-line maintenance treatment in patients with mild-moderate ulcerative colitis (UC). Early identification of patients at high risk for 5-ASA non-response, along with appropriate therapeutic escalation, are essential to avoid disease progression; however, the absence of a standardized definition for treatment success makes this task challenging. The focus of the current review is to describe the risk factors and management strategies associated with 5-ASA non-response. Rates of 5-ASA failure can vary from 17% to 75% according to different success definitions, of which clinical relapse is the most prevalent and studied condition. Younger age and endoscopic activity at diagnosis, extensive colitis, early need for corticosteroids, elevated inflammatory markers and non-adherence are consistent risk factors of 5-ASA failure. Given the effectiveness, safety profile and tolerability of this medication, therapy optimization is critical before treatment escalation. Combined use of systemic and topical therapy at appropriate doses in once-daily administration, along with control of adherence, could improve success rates.

BACKGROUND: Chemical sphincterotomy avoids the risk of permanent incontinence in the treatment of chronic anal fissure, but it does not reach the efficacy of surgery and recurrence is high. Drug combination has been proposed to overcome these drawbacks.; OBJECTIVE: This study aimed to compare the clinical, morphological, and functional effects of combined therapy with botulinum toxin injection and topical diltiazem in chronic anal fissure and to assess the long-term outcome after healing.; DESIGN: This is a randomized, controlled, double-blind, 2-arm, parallel-group trial with a long-term follow-up.; SETTINGS: This study was conducted at a tertiary care center.; PATIENTS: A total of 70 consecutive patients were referred to the gastroenterology department of a hospital in Valencia, Spain.; INTERVENTION: After botulinum toxin injection (20 IU), patients were randomly assigned to local diltiazem (diltiazem group) or placebo gel (placebo group) for 12 weeks.; MAIN OUTCOME MEASURES: The primary outcome was fissure healing (evaluated by video register by 3 independent physicians). Secondary outcomes included symptomatic relief (30-day diary), effect on anal sphincters (manometry), safety, and long-term recurrence (24 months and 10 years).; RESULTS: Healing was achieved per protocol in 13 of 25 (52%) patients of the diltiazem group and 11 of 30 (36.7%) patients of the placebo group (p = 0.25); on an intention-to-treat basis in 37.1% and 31.4% (p = 0.61). Both groups displayed significant reduction of anal pressures. Thirty percent reported minor and transitory incontinence, without differences between groups. Nine (69.2%) of the diltiazem group and 6 (54.5%) of the placebo group experienced a relapse at 24 months (p = 0.67). The overall recurrence rate at 10 years was 83.3% (20/24 patients).; LIMITATIONS: This study was limited by the loss of patients during the trial. The low healing rate led to a small cohort to assess recurrence.; CONCLUSIONS: Combined botulinum toxin injection and topical diltiazem is not superior to botulinum toxin injection in the treatment of chronic anal fissure. Both options offer suboptimal healing rates. Long-term recurrence is high (>80% at 10 years) and might appear at any time after healing. See Video Abstract at http://links.lww.com/DCR/B527.; INYECCIN DE TOXINA BOTULNICA MS DILTIAZEM TPICO EN FISURA ANAL CRNICA UN ENSAYO CLNICO ALEATORIZADO DOBLE CIEGO Y RESULTADOS A LARGO PLAZO: ANTECEDENTES:La esfinterotomia quimica evita el riesgo de incontinencia permanente en el tratamiento de la fisura anal cronica, pero no alcanza la eficacia de la cirugia y la recurrencia es alta. Se ha propuesto la combinacion de farmacos para superar estos inconvenientes.OBJETIVO:Comparar los efectos clinicos, morfologicos y funcionales de la terapia combinada con inyeccion de toxina botulinica y diltiazem topico en fisura anal cronica y evaluar el resultado a largo plazo despues de la cicatrizacion.DISENO:Ensayo aleatorizado, controlado, doble ciego, de dos brazos, de grupos paralelos con un seguimiento a largo plazo.ESCENARIO:Estudio realizado en un centro de atencion terciaria.PACIENTES:Un total de 70 pacientes consecutivos referidos al servicio de gastroenterologia de un hospital de Valencia, Espana.INTERVENCION:Despues de la inyeccion de toxina botulinica (20UI), los pacientes fueron asignados al azar a diltiazem local (grupo de diltiazem) o gel de placebo (grupo de placebo) durante 12 semanas.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue la cicatrizacion de la fisura (evaluado por registro de video por tres medicos independientes). Los resultados secundarios incluyeron alivio sintomatico (diario de 30 dias), efecto sobre los esfinteres anales (manometria), seguridad y recurrencia a largo plazo (24 meses y 10 anos).RESULTADOS:La curacion se logro por protocolo en 13/25 (52%) en el grupo de Diltiazem y 11/30 (36,7%) en el grupo de Placebo (p = 0.25); por intencion de tratar en el 37.1% y el 31.4%, respectivamente (p = 0.61). Ambos grupos mostraron una reduccion significativa de las presiones anales. El 30% refirio incontinencia leve y transitoria, sin diferencias entre grupos. 9 (69.2%) del grupo de Diltiazem y 6 (54.5%) del grupo de placebo recurrieron a los 24 meses (p = 0.67). La tasa global de recurrencia a los 10 anos fue del 83.3% (20/24 pacientes).LIMITACIONES:La perdida de pacientes a lo largo del ensayo. La baja tasa de curacion llevo a una pequena cohorte para evaluar la recurrencia.CONCLUSIONES:La inyeccion combinada de toxina botulinica y diltiazem topico no es superior a la inyeccion de TB en el tratamiento de la fisura anal cronica. Ambas opciones ofrecen tasas de curacion suboptimas. La recurrencia a largo plazo es alta (> 80% a los 10 anos) y puede aparecer en cualquier momento despues de la curacion. Consulte Video Resumen en http://links.lww.com/DCR/B527. Copyright © The ASCRS 2021.

This is the peer reviewed version of the following article: Changes in the requirement for early surgery in inflammatory bowel disease in the era of biological agents. Journal of Gastroenterology and Hepatology (2020): 29 April, which has been published in final form at https://doi.org/10.1111/jgh.15084. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions, Biological therapies may be changing the natural history of inflammatory bowel diseases, reducing the need for surgical intervention. We aimed to assess whether the availability of anti‐TNF agents impacts the need for early surgery in Crohn's disease (CD) and ulcerative colitis (UC). Methods Retrospective, cohort study of patients diagnosed within a 6‐year period before and after the licensing of anti‐TNFs (1990‐1995 and 2007‐2012 for CD; 1995‐2000 and 2007‐2012 for UC) were identified in the ENEIDA Registry. Surgery‐free survival curves were compared between cohorts. Results A total of 7,370 CD patients (2,022 in Cohort 1 and 5,348 in Cohort 2) and 8,069 UC patients (2,938 in Cohort 1 and 5,131 in Cohort 2) were included. Immunosuppressants were used significantly earlier and more frequently in both CD and UC post‐biological cohorts. The cumulative probability of surgery was lower in CD following anti‐TNF approval (16% and 11%, 22% and 16%, and 29% and 19%, at 1, 3 and 5 years, respectively p

Background Patients with inflammatory bowel disease (IBD) may present extraintestinal manifestations (EIMs) that affect the joints, skin, eyes, and hepatobiliary area, among others. Aims Our aim was to analyse the prevalence and characteristics of EIMs in patients with IBD and to identify the possible risk factors associated with the development of EIMs in the largest series published to date. Methods Observational, cross-sectional study including patients from the Spanish ENEIDA registry promoted by GETECCU. We retrospectively identified all cases of EIMs in the ENEIDA registry until January 2018. Results The study included 31,077 patients, 5779 of whom had at least one EIM (global prevalence 19%; 95% CI 18.2-19.0). Among the different types of EIMs, rheumatic manifestations had a prevalence of 13% (95% CI 12.9-13.7; 63% of EIMs), with a prevalence of 5% (95% CI 4.7-5.2) for mucocutaneous manifestations, 2.1% (95% CI 1.9-2.2) for ocular manifestations, and 0.7% (95% CI 0.6-0.8) for hepatobiliary manifestations. The multivariable analysis showed that the type of IBD (Crohn's disease,p < 0.001), gender (female,p < 0.001), the need for an immunomodulator (p < 0.001) or biologic drugs (p < 0.001), a previous family history of IBD (p < 0.001), and an extensive location of IBD (p < 0.001) were risk factors for the presence of EIMs. Conclusions One-fifth of patients with IBD may have associated EIMs, with rheumatic manifestations as the most frequent (> 60% of EIMs). Female patients with severe Crohn's disease represent the group with the highest risk of developing EIMs. These patients should therefore be specially monitored and referred to the corresponding specialist when suggestive symptoms appear.

Background The effectiveness of the switch to another anti–tumor necrosis factor (anti-TNF) agent is not known. The aim of this study was to analyze the effectiveness and safety of treatment with a second and third anti-TNF drug after intolerance to or failure of a previous anti-TNF agent in inflammatory bowel disease (IBD) patients. Methods We included patients diagnosed with IBD from the ENEIDA registry who received another anti-TNF after intolerance to or failure of a prior anti-TNF agent. Results A total of 1122 patients were included. In the short term, remission was achieved in 55% of the patients with the second anti-TNF. The incidence of loss of response was 19% per patient-year with the second anti-TNF. Combination therapy (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.8–3; P < 0.0001) and ulcerative colitis vs Crohn’s disease (HR, 1.6; 95% CI, 1.1–2.1; P = 0.005) were associated with a higher probability of loss of response. Fifteen percent of the patients had adverse events, and 10% had to discontinue the second anti-TNF. Of the 71 patients who received a third anti-TNF, 55% achieved remission. The incidence of loss of response was 22% per patient-year with a third anti-TNF. Adverse events occurred in 7 patients (11%), but only 1 stopped the drug. Conclusions Approximately half of the patients who received a second anti-TNF achieved remission; nevertheless, a significant proportion of them subsequently lost response. Combination therapy and type of IBD were associated with loss of response. Remission was achieved in almost 50% of patients who received a third anti-TNF; nevertheless, a significant proportion of them subsequently lost response.

Resumen Vedolizumab (VDZ), un anticuerpo monoclonal humanizado que se une especificamente a -α4β7-integrina, aprobado para el tratamiento de la enfermedad de Crohn (EC) y la colitis ulcerosa (CU), ha demostrado su eficacia en ensayos clinicos controlados. Objetivo Describir una poblacion tratada con VDZ y evaluar su efectividad y seguridad a largo plazo en practica clinica. Metodos Estudio observacional y multicentrico en pacientes con enfermedad inflamatoria intestinal tratados con VDZ durante al menos un ano. Se evaluaron los indices de actividad, niveles de calprotectina fecal y proteina C reactiva, hospitalizaciones, cirugias y eventos adversos. Resultados Se analizaron un total de 73 pacientes (43 CU y 30 EC). El 74 y 23% de CU y el 90 y 37% de EC habian llevado previamente mas de un anti-TNF y mas de un inmunosupresor respectivamente. VDZ se suspendio en 17 pacientes (23%), 10 CU y 7 EC, debido a la falta o perdida de respuesta antes del primer ano o a eventos adversos. Veintisiete (63%) CU y 16 (53%) pacientes con EC requirieron intensificacion de la dosis. A los 6 meses, el 70 y 42% de CU y el 80 y 43% de EC lograron respuesta clinica y remision respectivamente. Al ano, el 58 y 35% de CU y el 47 y 43% de EC mantuvieron la respuesta clinica y la remision, respectivamente. La proteina C reactiva disminuyo significativamente tanto en la EC como en la CU. Sin embargo, la disminucion de la calprotectina fecal se logro durante el seguimiento solo en CU pero no en EC. Ocho pacientes con EC que habian sido tratados previamente con ustekinumab evitaron la cirugia al ano. En 8 CU (18,6%) se realizo colectomia y 4 EC (13,3%) necesitaron cirugia. Seis pacientes (8%) (5 UC y una enfermedad de Crohn) tuvieron eventos adversos. El uso concomitante de corticoides o inmunomoduladores no aumento la efectividad. A mayor numero de anti-TNF previos, menos remision en la CU y respuesta en la EC. Conclusiones Tras un ano de VDZ se induce respuesta y remision clinica en una no desdenable proporcion de pacientes refractarios a diferentes biologicos o inmunosupresores. VDZ puede considerarse una alternativa en intolerantes a inmunosupresores con pocos eventos adversos.

Resumen Objetivos Establecer recomendaciones para el manejo de los aspectos psicologicos de los pacientes con enfermedad inflamatoria intestinal (EII). Metodos Se llevo a cabo una reunion con un grupo de expertos en EII formado por medicos, psicologos, enfermeras y representantes de pacientes. Se presentaron resultados de: 1) un grupo focal previo, 2) encuestas a medicos y pacientes y 3) una revision sistematica sobre instrumentos de cribado de ansiedad y depresion. Se realizo una discusion guiada sobre los aspectos psicologicos y emocionales mas importantes en EII, los criterios de derivacion apropiados y situaciones a evitar. Se selecciono el instrumento validado mas aplicable a la practica clinica. Se diseno un documento con recomendaciones, asi como una encuesta Delphi. La encuesta fue enviada al grupo y a un comite cientifico seleccionado del grupo GETECCU, con el objetivo de establecer el grado de apoyo a las recomendaciones establecidas. Resultados Se establecieron 15 recomendaciones, pertenecientes a 3 procesos clave: 1) que pasos dar para identificar problemas psicologicos en consulta de EII, 2) criterios de derivacion a profesionales de la salud mental y 3) abordaje de los problemas psicologicos. Conclusiones Se deben facilitar recursos a los profesionales sanitarios para que puedan tratar estos aspectos en consulta, identificar los trastornos que puedan afectar el curso de la enfermedad o su impacto en la vida del paciente, para ser tratados y seguidos por el profesional mas adecuado. Estas recomendaciones pueden servir de base para el rediseno de los servicios o procesos de EII y como justificacion para la formacion del personal sanitario.

Aim To determine the genetic predisposition to celiac disease (CeD) in inflammatory bowel disease (IBD) patients by quantifying the frequency of CeD-related human leucocyte antigen (HLA) (HLA-CeD: HLA-DQ2 and -DQ8) in IBD patients globally, by type of IBD and gender, and by calculating the protective/risk contribution of these haplotypes in the development of the IBD disease. Methods We conducted a prospective study with IBD patients from our Unit. Clinical information was gathered and blood was tested for HLA-CeD. The control group was made up of unrelated Valencian organ donors. Results 1034 subjects were analyzed: 457 IBD [207 ulcerative coliti (UC) and 250 Crohn's disease (CD)] patients and 577 healthy controls. 39% of the controls and 34% of the patients had HLA-CeD (P = 0.0852). HLA-DQ2 was less frequent in UC patients (P = 0.0287), and HLA-DQ8 in CD (P = 0.0217). In women with UC, the frequency of DQ2.5cis (DQB1*02:01-DQA1*05:01) was reduced ≥ 50% [P = 0.0344; preventive fraction (PF) = 13%]. PFs (7%-14%) were obtained with all HLA-CeD haplotypes. HLA DQB1*02:02-DQA1*02:01 (HLA-DQ2.2) was more frequent in CD patients with respect to controls (P = 0.001) and UC patients (etiological fraction = 15%). Conclusion HLA-CeD is not more frequent in IBD patients, with an even lower frequency of HLA-DQ2 and -DQ8 in UC and CD respectively. HLA-DQ2.5 confers protection from the development of UC, especially in women, and HLA-DQ8 does so for the appearance of CD. HLA-DQ2.2 is present in 34% of the CD patients and may constitute a genetic risk factor for CD development.

Background A less aggressive phenotype of Crohn’s disease (CD) has been reported in patients with elderly onset CD. Despite this, similar surgical rates among younger and older CD patients have been reported. However, scarce data are available about the risk of postoperative recurrence (POR) regarding the age, and no data are available about the use of immunosuppressants and biological agents for prevention of POR in elderly patients. Our aim was to evaluate the management of CD in the postoperative setting and the rate of surgical POR in CD patients according to the age at surgery. Methods Cohort study including all adult CD patients in the ENEIDA registry (a prospectively-maintained database of the Spanish Working Group in IBD –GETECCU-) who underwent a first intestinal resection with ileo-colonic anastomosis. Patients were grouped regarding their age at the moment of the first surgery: over 60 years (elderly) and between 18 and 60 years of age (controls). Preventive treatment for POR, surgical POR (need for a further intestinal resection) and postoperative morbidity were compared between both groups. Results Out of the 69,740 IBD patients included in the ENEIDA database, 3,982 had a first intestinal resection for Crohn’s disease with an ileo-colonic anastomosis between 2005 and 2020. Of them, 535 were elderly and 3,454 controls. Time from IBD diagnosis to surgery was significantly longer in the elderly (114±128 vs. 93±97 months; p Conclusion The elderly patients show similar rates of surgical POR as compared to younger patients. Given the high risk of thiopurine and anti-TNF-related adverse events, elderly patients with inflammatory pattern would benefit from preventive therapy with safer biologicals.

Background Patients with colon Inflammatory Bowel Disease (IBD) have a higher risk of colorectal cancer (CRC) than general population. Current guidelines establish endoscopic surveillance recommendations; however, epidemiological studies show poor compliance. The main aim of our study was to analyse adherence to endoscopic surveillance guidelines. Secondary aim was to evaluate the prevalence and time-to advanced lesions or CRC. Methods Retrospective multicentre study of patients with IBD followed-up in the participating centres between 2005 and 2020, who were diagnosed of IBD between 2005 and 2008, with criteria for CRC surveillance. Patients with CRC before IBD diagnosis were excluded. The ECCO 2013–2017 guidelines were used to evaluate adherence. Adenomatous lesions with >25% of villous component, >1cm or with high-grade dysplasia or serrated lesions >1cm or with any degree of dysplasia were considered advanced lesions. Software used for all analysis was R in its 3.6.1 version. Normality was checked with the Shapiro-Wilks test. Mean comparison was carried out using t-Student test while normality assumptions held true, otherwise, Mann-Whitney test. Time-to advanced lesions or CRC event between patients that had adherence to ECCO guidelines versus those who did not was performed through Kaplan-Meier and Log-rank test. P-values below 0.05 were considered significant. Results A total of 1004 (713 Ulcerative Colitis, 252 Crohn’s disease and 39 Indeterminate Colitis; 52% male) patients from 25 centres were recruited with a median age of 36 (26–47) years. 87% of all patients were included in the endoscopic surveillance programme. The main reasons for non-inclusion were the absence of indication by the physician (38%) and the presence of inflammatory activity (37%). Adherence to the first or subsequent surveillance colonoscopies was 45% and 61%, respectively, with a total adherence rate of 32%. Prevalence of advanced lesions or CRC was 4% and 7 cases of CRC were detected. Time-to-detection of these lesions since IBD diagnosis was significantly longer in non-adherent patients (13.4 + 1.3 vs13.04 + 1.7; p Conclusion Adherence to ECCO guidelines for endoscopic surveillance is low in this Southern European population. A higher and earlier detection of advanced lesions or CRC was identified in the adherent group. The results of this study highlight the need to improve compliance with the recommendations to obtain better outcomes.

En esta Guía de práctica clínica analizamos el manejo diagnóstico y terapéutico de pacientes adultos con estreñimiento y molestias abdominales, bajo la confluencia del espectro del síndrome del intestino irritable y el estreñimiento funcional. Ambas patologías están encuadradas en los trastornos funcionales intestinales y tienen una importante repercusión personal, sanitaria y social, afectando a la calidad de vida de los pacientes que las padecen. La primera es el subtipo de síndrome del intestino irritable en el que el estreñimiento es la alteración deposicional predominante junto con dolor abdominal recurrente, hinchazón y distensión abdominal frecuente. El estreñimiento se caracteriza por la dificultad o la escasa frecuencia en relación con las deposiciones, a menudo acompañado por esfuerzo excesivo durante la defecación o sensación de evacuación incompleta. En la mayoría de los casos no tiene una causa orgánica subyacente, siendo considerado un trastorno funcional intestinal. Son muchas las similitudes clínicas y fisiopatológicas entre ambos trastornos, con respuesta similar del estreñimiento a fármacos comunes, siendo la diferencia fundamental la presencia o ausencia de dolor, pero no de un modo evaluable como «todo o nada». La gravedad de estos trastornos depende no solo de la intensidad de los síntomas intestinales sino también de otros factores biopsicosociales: asociación de síntomas gastrointestinales y extraintestinales, grado de afectación, y formas de percepción y comportamiento. Mediante los criterios de Roma, se diagnostican los trastornos funcionales intestinales. Esta Guía de práctica clínica está adaptada a los criterios de Roma IV difundidos a finales de mayo de 2016. En una primera parte (96, 97, 98) se analizaron los aspectos conceptuales y fisiopatológicos, los criterios de alarma, las pruebas diagnósticas y los criterios de derivación entre Atención Primaria y aparato digestivo. En esta segunda parte, se revisan todas las alternativas terapéuticas disponibles (ejercicio, ingesta de líquidos, dieta con alimentos ricos en fibra soluble, suplementos de fibra, otros componentes de la dieta, laxantes osmóticos o estimulantes, probióticos, antibióticos, espasmolíticos, esencia de menta, prucaloprida, linaclotida, lubiprostona, biofeedback, antidepresivos, tratamiento psicológico, acupuntura, enemas, neuroestimulación de raíces sacras o cirugía), efectuando recomendaciones prácticas para cada una de ellas.

Background INFEII registry (ClinicalTrials.gov: NCT02904590) is a prospective study promoted by GETECCU to determine the incidence and risk factors of infection in an inception cohort of IBD patients. Despite preventive measures and recommendations of scientific societies, TB remains a problem in patients with IBD treated with immunosuppressants (IMM) and biologics. AIMS To asses: (1) the screening of TB performed at the time of inclusion of a patient in the INFEII registry, (2) the incidence of latent TB; and (3) compliance with national and European recommendations. Methods A longitudinal prospective study of incident cases with IBD, initiated in October 2016 and with a planned follow-up of 5 years. In September 2019, INFEII registry had 1241 patients from 28 centres throughout Spain. The study protocol determines the mandatory fulfilment of TB screening in every patient, leaving to the centre the freedom of decision on what procedures to perform. Guidelines recommend a mandatory study before starting immunosuppression, especially with biological treatment, using the combination of tuberculin skin test (TST) and interferon-gamma release assay (IGRA) or at least one TST with a booster test1,2. Results Of the 1241 patients 233 (19%) had no screening, 494 (40%) had one [TST 158, IGRA 299, thorax-X-ray 37], 288 (23%) two [TST + IGRA 87, IGRA + thorax-X-ray 130, TST + thorax-X-ray 30, TST + booster 41], 128 (10%) three [TST + IGRA + thorax-X-ray 65, TST + booster + IGRA 23, TST + booster + thorax-X-ray 40] and 98 (7.9%) the four tests [TST + booster + IGRA + thorax-X-ray]. 486 patients (48%) receive pharmacological immunosuppression (172 IMMS, 195 biologics, 119 COMBO) and from them 198 (41%) followed the guidelines recommendation (131 TST and IGRA and 118 TST-booster), 245 (50%) had some method for TB screening [TST 43, IGRA 112, thorax-X-ray 15, IGRA + thorax-X-ray 57, TST + thorax-X-ray 18] and 43 patients (8.8%) had no screening. With the baseline screening, latent TB was detected in 134 patients (13%), 63 (47%) receiving anti-TB chemotherapy. In patients initiating immunosuppression, latent TB was detected in 35 cases [of which 28 received prophylaxis but 7 under IMM did not]. Active TB was detected in 4 cases: 2 during baseline screening, one without screening and one with negative screening (negative TST and IGRA, without booster receiving biological treatment). Conclusion Despite TB in IBD is a relevant problem, there is ample room for improvement for the implementation of mandatory minimum screening recommendations, even in prospective protocolised projects. References

Background:Linaclotide is approved for the treatment of moderate-to-severe irritable bowel syndrome (IBS) with constipation (IBS-C) in adults. This study aimed to assess factors predictive of a clinical response and improvements in non-IBS symptoms with linaclotide treatment in a Spanish patient population.Methods:In this open-label phase IIIb study, patients with moderate-to-severe IBS-C received linaclotide 290 μg once daily for 12 weeks. The primary endpoint was clinical response at week 12, defined as >30% reduction in IBS symptom severity score (IBS-SSS) or IBS-SSS Results:A total of 96 patients were eligible; 91 were female and the mean age was 47.4 years. Mean (SD) baseline IBS-SSS was 371 (72.5). In the intention-to-treat and per-protocol populations, 22.9% and 31.7% were clinical responders at week 4, respectively, and 25.0% and 36.7% were clinical responders at week 12. Digestive nonintestinal and extra-digestive symptom scores were significantly improved at weeks 4 and 12. Baseline characteristic was not associated with week 12 clinical response; however, clinical response at week 4 was predictive of response at week 12 (OR: 6.5; 95%IC: 2.1–19.8). The most common adverse event was diarrhea inclusive of loose or watery stools (35.4%).Conclusions:Linaclotide improves IBS-C symptoms, including digestive nonintestinal and extra-digestive symptoms. A clinical response at week 4 may predict response at week 12.

Immunosuppressant therapies (IMTs; thiopurines, anti-tumor necrosis factor agents) may influence the immunologic control of cancer and might facilitate the spread and recurrence of cancer. This study assesses the impact of the use of IMTs on the development of incident cancers (recurrent or new) in patients with inflammatory bowel disease (IBD) and a history of malignancy.Patients with IBD included in the ENEIDA registry with a history of cancer without being exposed to IMTs were identified and retrospectively reviewed and compared regarding further treatment with IMTs or not by means of a log-rank test.Overall, 520 patients with previous extracolonic cancer naive to IMTs before the diagnosis of cancer were identified. Of these, 146 were subsequently treated with IMTs (exposed), whereas 374 were not (nonexposed). The proportion of patients with incident cancers was similar in both exposed (16%) and nonexposed (18%) patients (P = 0.53); however, there was more than a 10-year difference in the age at index cancer between these 2 groups. Cancer-free survival was 99%, 98%, and 97% at 1, 2, and 5 years in exposed patients, and 97%, 96%, and 92% at 1, 2, and 5 years in non-exposed patients, respectively (P = 0.03). No differences in incident cancer rates were observed between exposed and nonexposed patients when including only those who were exposed within the first 5 years after cancer diagnosis.In patients with IBD and a history of cancer not related to immunosuppression, the use of IMTs is not associated with an increased risk of new or recurrent cancers even when IMTs are started early after cancer diagnosis.

To determine the impact of non-adherence to 5-Aminosalicylates (5-ASA) on the risk of flares and to identify risk factors of non-adherence. Observational, cohort study of ulcerative colitis (UC) patients in clinical remission at least 6 months on 5-ASA monotherapy maintenance prescribed by an electronic management program. Adherence was considered when 80% of the prescribed 5-ASA had been dispensed at the pharmacy. The study analyzed the existence and degree of 5-ASA adherence, disease course, UC phenotypic expression, and 5-ASA dose and regimen, and consumption of non-UC chronic drugs during 2-year follow-up. The study included 274 patients, 49% males with a median age of 38 (27–49) years old. Overall, 41% of patients were non-adherent to 5-ASA. Risk of flares was reduced in the adherent group (36% vs 54%; OR = 0,484; p = 0,004), mainly the mild ones (26% vs 38%; OR = 0,559; p = 0,031). Non-adherence was associated with younger age at diagnosis (32 (26–45) vs 41.5 (21–50), p = 0.000) and no-consumption of other chronic treatments (1.1 vs 2.1; OR = 1709; p = 0,048). Non-adherence to 5-ASA evaluated by the pharmaceutical management system was at 41% with a higher risk of relapse. Younger patients and patients who do not receive non-UC chronic treatments showed lower adherence rate.

BackgroundThe benefits of immunosuppressants for sustaining remission and preventing flares of IBD are well known. However, optimal timing for withdrawal has not been determined.AimsThe objective of this study was to calculate the risk of relapse and predictors after withdrawal of azathioprine (AZA) monotherapy in patients who sustain deep remission.MethodsThis was a multicenter observational study of patients with IBD in remission whose immunosuppressant had been withdrawn. We recorded demographic variables, disease data, laboratory values, and the results of imaging tests performed at withdrawal and, in patients who relapsed, time to relapse and the efficacy of reintroducing the drug.ResultsNinety-five patients were included (35 UC and 60 CD). The mean duration of AZA treatment was 87 and 77months for UC and CD, respectively. Endoscopic remission was evaluated in 23 patients with UC and 35 with CD. After AZA withdrawal, 91% patients with UC and 67% with CD received high doses of salicylates. A total of 26 patients relapsed. The cumulative relapse rate at 5years was 46% for CD and UC. AZA was reintroduced in 19 patients, of whom 14 responded. Predictors of relapse were corticosteroid dependence, early introduction of AZA (CD), and late introduction of AZA (UC).ConclusionsAlmost half of the patients in whom AZA was withdrawn were in remission at 5years. The candidates for withdrawal could be better identified based on corticosteroid dependence, previous surgery, timing of initiation, and indication for AZA.

Background: Recent evidence endorses gut microbiota dysregulation in the pathophysiology of heart failure (HF). Small intestinal bacterial overgrowth (SIBO) might be present in HF and associated with poor clinical outcomes. Lactulose breath testing is a simple noninvasive test that has been advocated as a reliable indicator of SIBO. In patients with HF, we aimed to evaluate the association with clinical outcomes of the exhaled hydrogen (H-2) and methane (CH4) concentrations through the lactulose breath test. Methods and Results: We included 102 patients with HF in which lactulose SIBO breath tests were assessed. Cumulative gas was quantified by the area under the receiver operating characteristic curve of CH4 (AUC-CH4) and H-2 (AUC-H-2). Clinical end points included the composite of all-cause death with either all-cause or HF hospitalizations, recurrent all-cause hospitalizations, and recurrent HF hospitalizations. Medians (interquartile ranges) of AUC-H-2 and AUC-CH4 were 1290 U (520-2430) and 985 U (450-2120), respectively. In multivariable analysis, AUC-H-2 (per 1000 U) was associated with all-cause death/all-cause hospitalization (hazard ratio [HR] 1.21, 95% CI 1.04-1.40; P = .012), all-cause death/HF hospitalization (HR 1.20, 95% CI 1.03-1.40; P = .021), and an increase in the rate of recurrent all-cause (incidence rate ratio [IRR] 1.31, 95% CI 1.14-1.51; P < .001) and HF (IRR 1.41, 95% CI 1.15-1.72; P = .001) hospitalizations. AUC-CH4 was not associated with any of these end points. Conclusions: AUC-H-2, a safe and noninvasive method for SIBO estimation, is associated with higher risk of long-term adverse clinical events in patients with HF. In contrast, AUC-CH4 did not show any prognostic value.

Background: In APPRECIA trial, Crohn's disease (CD) patients undergoing intestinal resection were randomized to postoperative adalimumab (ADA) or azathioprine (AZA). Aims: To evaluate health-related quality of life (HRQoL) in APPRECIA trial. Methods: HRQoL was evaluated using disease-specific shortened Spanish version of the IBDQ (SIBDQ-9) and generic European Quality of Life-5 Dimensions (EQ-5D) questionnaires, completed at baseline and at weeks 24 and 52. Results: Sixty-one patients (37 ADA and 24 AZA) had evaluable data for HRQoL. Patients treated with ADA or AZA had significant improvement from baseline to weeks 24 and 52 in SIBDQ-9 and EQ-5D (p < 0.001 and p = 0.006 for all comparisons, respectively). There were no differences between treatment arms in mean change in SIBDQ-9 and EQ-5D at weeks 24 and 52 vs baseline. Only patients without endoscopic recurrence had significant improvement in SIBDQ-9 (p < 0.001) and EQ-5D (p < 0.001) at week 52. At week 52, there was a high to moderate negative correlation between CDAI score with SIBDQ-9 score( Pearson's r: -0.768) and with EQ-5D index (r: -0.644). Conclusion: HRQoL improved after intestinal resection in CD, irrespective of the postoperative therapyused (ADA or AZA). Outcomes in HRQoL were associated with prevention of endoscopic recurrence, sinceimprovements in HRQoL were only significant in patients with endoscopic remission at 1 year. (c) 2019 Editrice Gastroenterologica Italiana S. r. l. Published by Elsevier Ltd. All rights reserved.

Background:Tocilizumab (TCZ) has shown to be effective for large vessel vasculitis including Takayasu arteritis (TAK) (1-3). Most evidence in TAK comes from Asian patients. However, white patients seem to have different clinical and prognostic features.Objectives:Our aims were to: a) assess the efficacy and safety of TCZ in white patients with refractory TAK, b) determine if clinical improvement correlates with imaging outcomes, c) compare TCZ in monotherapy (TCZMONO) vs combined with conventional immunosuppressive drugs (TCZCOMBO)Methods:Multicenter study of white patients with refractory TAK who received TCZ.Outcomes variables were remission, glucocorticoid-sparing effect, improvement in imaging techniques, and adverse events. A comparative study between patients who received TCZMONO and TCZCOMBO was performed.Results:54 patients (46 women/8 men; median age 42.0 [32.5-50.5] years). TCZ was started after 12.0 [3.0-31.5] months since TAK diagnosis. Remission was achieved in 12/54 (22.2%), 19/49 (38.8%), 23/44 (52.3%) and 27/36 (75%) at 1, 3, 6 and 12 months, respectively. Prednisone dose was reduced from 30.0 [12.5-50.0] to 5.0 [0.0-5.6] mg/day at 12 months (Table 1). 10 (26.3%) of the 38 patients in whom an imaging follow-up test was performed showed no radiographic improvement after a median of 9.0 [6.0-14.0] months. 4 of them were in clinical remission.23 (42.6%) patients were on TCZMONO and 31 (57.4%) on TCZCOMBO: MTX (n=28), cyclosporine A (n=2), azathioprine (n=1). Patients on TCZCOMBO were younger (38.0 [27.0-46.0] vs 45 [38.0-57.0] years; p= 0.048), with a trend to longer TAK duration (21.0 [6.0-38.0] vs 6.0 [1.0-23.0] months; p= 0.08) and higher C-reactive protein (2.4 [0.7-5.6] vs 1.3 [0.3-3.3] mg/dL; p=0.16). Despite these differences, similar outcomes were observed in both groups (log rank p=0.862) (Figure 1). Relevant adverse events were reported in 6 (11.1%) patients, but only 3 developed severe events that required TCZ withdrawal.Table 1.Baselinen=54Month 1N=54Month 3N=49Month 6N=44Month 12N=36Clinical remission, n (%)12 (22.2)19 (38.8)23 (52.3)27 (75.0)Laboratory improvementCRP (mg/dL), median [IQR]1.5 [0.5-3.5]0.2 [0.1-0.7]*0.2 [0.5-0.5]*0.2 [0.1-0.5]*0.1 [0.0-0.4]*ESR (mm/1sthour), median [IQR]30.5 [8.7-52.7]7.0 [3.0-14.0]*4.5 [2.0-8.0]*5.0[2.0-6.0]*4.0 [2.0-9.5]*Hemoglobin (g/dL), mean ± SD12.4 ±1.513.0 ±1.2*13.0 ±1.4*13.2 ±1.5*12.9 ±1.6*Prednisone dose, median [IQR]30.0 [12.5-50.0]20.0 [10.0-30.0]*10.0 [5.0-20.0]*5.0 [5.0-10.5]*5.0 [0.0-5.6]*CRP: C-Reactive Protein; ESR: Erythrocyte Sedimentation Rate; IQR: interquartile range; n: number. *pConclusion:TCZ is effective and safe in white patients with refractory TAK. A discordance between clinical and imaging activity assessment may exist.References:[1]Prieto Peña D et al. Clin Exp Rheumatol 2020 Nov 27. PMID: 33253103.[2]Loricera J, et al. Clin Exp Rheumatol 2016; 34:S44-53. PMID: 27050507.[3]Calderón-Goercke M, et al. Semin Arthritis Rheum 2019; 49:126-35. PMID: 30655091Disclosure of Interests:Diana Prieto-Peña Grant/research support from: DP-P has received research support from UCB Pharma, Roche, Sanofi, Pfizer, AbbVie and Lilly., Pilar Bernabéu: None declared, Paloma Vela-Casasempere: None declared, J. Narváez: None declared, Carlos Fernández-López: None declared, Mercedes Freire González: None declared, Beatriz González-Alvarez: None declared, Roser Solans-Laqué: None declared, Jose Luis Callejas-Rubio: None declared, Norberto Ortego: None declared, Carlos Fernández-Díaz: None declared, Esteban Rubio Romero: None declared, SALVADOR GARCÍA MORILLO: None declared, Mauricio Minguez: None declared, Cristina Fernández-Carballido: None declared, Eugenio de Miguel: None declared, Sheila Melchor: None declared, Eva Salgado-Pérez: None declared, Beatriz Bravo: None declared, Susana Romero-Yuste: None declared, Juan Salvatierra: None declared, Cristina Hidalgo: None declared, Sara Manrique Arija: None declared, C. Romero-Gómez: None declared, Patricia Moya: None declared, Noelia Alvarez-Rivas: None declared, Javier Mendizabal: None declared, Francisco Miguel Ortiz Sanjuan: None declared, I. Pérez de Pedro: None declared, JOSE LUIS ALONSO VALDIVIESO: None declared, Pérez Sánchez Laura: None declared, Roldán Molina Rosa: None declared, Nagore Fernández-Llanio: None declared, Ricardo Gómez de la Torre: None declared, Silvia Suarez: None declared, María Jesús Montesa: None declared, Monica Delgado Sanchez: None declared, J. Loricera: None declared, Belén Atienza-Mateo: None declared, Santos Castañeda: None declared, Miguel A González-Gay Grant/research support from: MAG-G received grants/research supports from Abbvie, MSD, Jansen and Roche and had consultation fees/participation in company sponsored speaker´s bureau from Abbvie, Pfizer, Roche, Sanofi, Lilly, Celgene and MSD, Ricardo Blanco Grant/research support from: RB received grants/research supports from Abbvie, MSD and Roche, and had consultation fees/participation in company sponsored speaker´s bureau from Abbvie, Lilly, Pfizer, Roche, Bristol-Myers, Janssen, UCB Pharma and MSD.

Resumen En esta Guía de práctica clínica analizamos el manejo diagnóstico y terapéutico de pacientes adultos con estreñimiento y molestias abdominales, bajo el espectro del síndrome del intestino irritable y el estreñimiento funcional. Tienen una importante repercusión personal, sanitaria y social, afectando a la calidad de vida de los pacientes que las padecen. En el síndrome del intestino irritable con predomino del estreñimiento, este es la alteración deposicional predominante junto con dolor abdominal recurrente, hinchazón y distensión abdominal frecuente. El estreñimiento se caracteriza por la dificultad o la escasa frecuencia en las deposiciones, acompañado por esfuerzo excesivo durante la defecación o sensación de evacuación incompleta. La mayoría no tienen una causa orgánica subyacente, considerándose un trastorno funcional intestinal. Poseen muchas similitudes clínicas y fisiopatológicas, con respuesta similar del estreñimiento a fármacos comunes. La diferencia fundamental es la presencia o ausencia de dolor, pero no de un modo evaluable como «todo o nada». La gravedad depende tantro de la intensidad de los síntomas intestinales como de otros factores: asociación de síntomas gastrointestinales y extraintestinales, grado de afectación, formas de percepción y comportamiento. Los criterios de Roma diagnostican los trastornos funcionales intestinales. Esta Guía está adaptada a los criterios de Roma IV (mayo de 2016) y analiza, en esta primera parte, los criterios de alarma, las pruebas diagnósticas y los criterios de derivación entre Atención Primaria y Aparato Digestivo. En una segunda parte, se revisarán las alternativas terapéuticas disponibles (ejercicio, dieta, tratamientos farmacológicos, neuroestimulación de raíces sacras o cirugía), efectuando recomendaciones prácticas para cada una de ellas.

Background:Tocilizumab (TCZ) was recently approved for Takayasu Arteritis (TAK) in Japan based on the results of the TAKT trial(1).However, data in clinical practice in Europe and America are scarce(2).Objectives:To assess efficacy and safety of TCZ in TAK of clinical practice in Spain.Methods:Observational, open-label multicentre study of 53 TAK patients treated with TCZ due to refractoriness or adverse events of previous therapy. Outcomes variables were improvement of clinical features, acute phase reactants and glucocorticoid-sparing effect.Results:53 patients (46w/7m); mean age, 40.6±14.6 years at TCZ onset. TCZ was started after a median of 12 [3.0-48.0] months from TAK diagnosis. In addition to systemic corticosteroids and before TCZ they received conventional immunosuppressant drugs (n=42) and biologic therapy (n=14). TCZ was prescribed as standard I.V. (n=42; 79.2%) or subcutaneous (n=11; 20.8%). The initial dose was 8 mg/kg/IV/4 weeks or 162 mg/SC/week, respectively. TCZ was used in monotherapy or combined with immunosuppressants (n=32; 60.4%): methotrexate (n=27), azathioprine (n=2), cyclosporine (n=3). Main clinical features at TCZ onset were: malaise (n=30),limb claudication (n=22), headache (n=18), fever (n=14), abdominal pain (n=10), and chest pain (n=9). Most of the patients experienced a rapid and maintained clinical, analytical improvement(TABLE).After a median follow-up of 18.0 [7.0-45.0] months, TCZ was discontinued in 20 patients due to: sustained remission (n=6), relapse (n=6), adverse event (n=5), gestation (n=3). Most relevant adverse side effects were serious infections: pneumonia (n=2), herpes zoster (n=1), abdominal sepsis (n=1).Table.Basal(N=53)Month 1(N=53)Month 3(N=46)Month 6(N=44)Month 12(N=34)Clinical improvement, n/N(%)Complete17/53 (32.1)19/46 (41.3)23/44 (52.3)26/34 (76.5)Partial30/53 (54.6)26/46 (56.5)18/44 (40.9)8/34 (23.5)No improvement6/53 (11.3)1/46 (2.2)3/44 (6.8)0/34 (0.0)Analytical markers,ESR (mm/1sth),median [IQR]35.0 [16.0-52.0]7.5 [3.0-14.0] *3.5 [2.0-8.0]*5.0[2.0-6.0]*5.0 [2.0-8.5]*CRP (mg/dL),median [IQR]1.7 [0.6 -3.5]0.21 [0.05-0.6]*0.14 [0.05-0.5]*0.14 [0.04-0.4]*0.10 [0.03-0.30]*Hb (g/dL),mean±SD12.3±1.512.8±1.2*12.9±1.3*12.9±1.4*12.9±1.4*Prednisone dose (mg/day),median [IQR]30.0 [15.0-50.0]20.0 [10.0-37.5]*10.0 [5.0-20.0]*5.0 [5.0-12.5]*5.0 [0.0-7.5]**Wilcoxon test p < 0.001.Conclusion:TCZ appears to be effective and safe in patients with refractory TAK in clinical practice.References:[1]Nakaoka Y et al. Ann Rheum Dis. 2018;77:348-354[2]Loricera J et al. Clin Exp Rheumatol. 2016; 34: S44-53.Disclosure of Interests:D. Prieto-Peña: None declared, Monica Calderón-Goercke: None declared, Pilar Bernabéu: None declared, Paloma Vela-Casasempere: None declared, J. Narváez: None declared, Carlos Fernández-López: None declared, Mercedes Freire González: None declared, Beatriz González-Alvarez: None declared, Roser Solans-Laqué: None declared, Jose Luis Callejas-Rubio: None declared, Norberto Ortego: None declared, Carlos Fernández-Díaz Speakers bureau: Brystol Meyers Squibb, Esteban Rubio Romero: None declared, SALVADOR GARCÍA MORILLO: None declared, Mauricio Minguez: None declared, Cristina Fernández-Carballido Consultant of: Yes, I have received fees for scientific advice (Abbvie, Celgene, Janssen, Lilly and Novartis), Speakers bureau: Yes, I have received fees as a speaker (Abbvie, Celgene, Janssen, Lilly, MSD, Novartis), Eugenio de Miguel Grant/research support from: Yes (Abbvie, Novartis, Pfizer), Consultant of: Yes (Abbvie, Novartis, Pfizer), Paid instructor for: yes (AbbVie, Novartis, Pfizer, MSD, BMS, UCB, Roche, Grunental, Janssen, Sanofi), Speakers bureau: yes (AbbVie, Novartis, Pfizer, MSD, BMS, UCB, Roche, Grunental, Janssen, Sanofi), Sheila Melchor: None declared, Eva Salgado-Pérez: None declared, Beatriz Bravo: None declared, Susana Romero-Yuste: None declared, J Salvatierra: None declared, Cristina Hidalgo: None declared, Sara Manrique Arija: None declared, C. Romero-Gómez: None declared, Patricia Moya: None declared, Noelia Alvarez-Rivas: None declared, Javier Mendizabal: None declared, Francisco Miguel Ortiz Sanjuan: None declared, I. Pérez de Pedro: None declared, Javier Loricera: None declared, Santos Castañeda: None declared, Miguel A González-Gay Grant/research support from: Pfizer, Abbvie, MSD, Speakers bureau: Pfizer, Abbvie, MSD, Ricardo Blanco Grant/research support from: AbbVie, MSD, Roche, Consultant of: Abbvie, Eli Lilly, Pfizer, Roche, Bristol-Myers, Janssen, UCB Pharma and MSD, Speakers bureau: Abbvie, Eli Lilly, Pfizer, Roche, Bristol-Myers, Janssen, UCB Pharma. MSD

Inhibition of BACE1 has become an important strategy in the quest for disease modifying agents to slow the progression of Alzheimer's disease. We previously reported the fragment-based discovery of LY2811376, the first BACE1 inhibitor reported to demonstrate robust reduction of human CSF Aβ in a Phase I clinical trial. We also reported on the discovery of LY2886721, a potent BACE1 inhibitor that reached phase 2 clinical trials. Herein we describe the preparation and structure activity relationships (SAR) of a series of BACE1 inhibitors utilizing trans-cyclopropyl moieties as conformational constraints. The design, details of the stereochemically complex organic synthesis, and biological activity of these BACE1 inhibitors is described.

RESUMEN Los trastornos motores y funcionales anorrectales son frecuentes en la población general. La manometría anorrectal permite estudiar la actividad motora anorrectal en reposo y simulando diferentes situaciones fisiológicas. La manometría anorrectal de alta resolución (MAR-AR) y de alta definición (MAR-AD) están utilizándose cada vez con más frecuencia en la práctica clínica. Con respecto a la técnica convencional, los catéteres de la MAR-AR y los de la MAR-AD proporcionan un mayor número de puntos de registro, ya que disponen de muchos sensores circunferenciales muy próximos entre sí. Ello permite la visualización en relación témporo-espacial (modo topográfico en 2 o 3 planos) al obtener un registro de presión continuo en el espacio por interpolación entre sensores muy próximos. La MAR-AR y la MAR-AD nos permiten realizar la técnica de una forma más estandarizada y reproducible y obtener un mejor estudio y comprensión de la anatomía funcional del complejo esfinteriano. Están desarrollándose nuevos parámetros específicos apropiados para utilizarse en la actualidad con estos sistemas y están siendo evaluados por diversos grupos de investigación, por lo que muchos de ellos no están disponibles para utilizarse en la práctica clínica. No obstante, aportan información muy relevante que está permitiendo redefinir la anatomía y la fisiología anorrectales. El objetivo de la presente revisión es describir las técnicas existentes para MAR-AR y MAR-D, exponer los valores publicados de normalidad y analizar los nuevos parámetros que estas técnicas permiten evaluar y que, posiblemente, en un futuro próximo serán de gran utilidad en la práctica clínica. ABSTRACT Anorectal motor and functional disorders are common among the general population. Anorectal manometry allows the study of anorectal motor activity both at rest and mimicking different physiological situations. High-resolution anorectal manometry (HR-ARM) and high-definition anorectal manometry (HD-ARM) are increasingly used in clinical practice. In comparison with the conventional technique, HR-ARM and HD-ARM catheters provide a higher number of recording points because of their many, closely packed circumferential sensors. This allows time-space visualization (topographic or 2-3-plane mode) as spatially continuous measurements are obtained by interpolation between near sensors. HR-ARM and HD-ARM allow a more standardized, reproducible technique, and a better assessment and understanding of the functional anatomy of the sphincter complex. Newer specific parameters are now being developed for use with these systems. They are being currently assessed by multiple research teams, and many of them remain unavailable for clinical practice as of today. However, they provide highly relevant information, which is now prompting a redefinition of anorectal anatomy and physiology. The goal of the present review was to describe the currently available HR-ARM and HD-ARM techniques, to discuss the normal values so far reported, and to analyze the newer parameters that may be assessed with these techniques, and which will likely be highly useful for clinical practice in the upcoming future.