Guía GADECCU 2022 para el tratamiento de la colitis ulcerosa. Adaptación y actualización de la guía GETECCU 2020

Ulcerative colitis (UC) is a chronic inflammatory disease that compromises the colon, affecting the quality of life of individuals of any age. In practice, there is a wide spectrum of clinical situations. The advances made in the physio pathogenesis of UC have allowed the development of new, more effective and safer therapeutic agents. To update and expand the evaluation of the efficacy and safety of relevant treatments for remission induction and maintenance after a mild, moderate or severe flare of UC. Gastroenterologists, coloproctologists, general practitioners, family physicians and others health professionals, interested in the treatment of UC. GADECCU authorities obtained authorization from GETECCU to adapt and update the GETECCU 2020 Guide for the treatment of UC. Prepared with GRADE methodology. A team was formed that included authors, a panel of experts, a nurse and a patient, methodological experts, and external reviewers. GRADE methodology was used with the new information. A 118-page document was prepared with the 44 GADECCU 2022 recommendations, for different clinical situations and therapeutic options, according to levels of evidence. A section was added with the new molecules that are about to be available. This guideline has been made in order to facilitate decision-making regarding the treatment of UC, adapting and updating the guide prepared by GETECCU in the year 2020.

La colitis ulcerosa (CU) es una enfermedad inflamatoria crónica que compromete el colon, afectando la calidad de vida de individuos de cualquier edad. Existe un amplio espectro de situaciones clínicas. Los avances realizados en fisiopatogenia de la CU han permitido desarrollar nuevos agentes terapéuticos más efectivos y seguros. Actualizar y ampliar la evaluación de la eficacia y seguridad de los tratamientos relevantes para la inducción de la remisión y el mantenimiento luego de un brote leve, moderado o grave de CU. Gastroenterólogos, coloproctólogos, médicos clínicos, médicos de familia y otros profesionales de la salud, interesados en el tratamiento de la CU. Las autoridades de GADECCU obtuvieron la autorización de GETECCU para la adaptación y actualización de la «Guía GETECCU 2020 para el tratamiento de la CU. Elaborada con metodología GRADE¼. Se conformó un equipo que incluyó a autores, panel de expertos, enfermera y un paciente, expertos en metodología y revisores externos. Se utilizó metodología GRADE con la nueva información. Se elaboró un documento de 118 páginas con las 44 recomendaciones GADECCU 2022, para distintas situaciones clínicas y opciones terapéuticas, según niveles de evidencia. Se agregó un apartado con las nuevas moléculas próximas a estar disponibles. Esta guía ha sido realizada con el fin de facilitar la toma de decisiones relativas al tratamiento de la CU, adaptando y actualizando la guía elaborada por GETECCU en el año 2020.

GADECCU 2022 Guideline for the treatment of Ulcerative Colitis. Adaptation and updating of the GETECCU 2020 Guideline. / Guía GADECCU 2022 para el tratamiento de la colitis ulcerosa. Adaptación y actualización de la Guía GETECCU 2020.

INTRODUCTION: Ulcerative colitis (UC) is a chronic inflammatory disease that compromises the colon, affecting the quality of life of individuals of any age. In practice, there is a wide spectrum of clinical situations. The advances made in the physio pathogenesis of UC have allowed the development of new, more effective and safer therapeutic agents. OBJECTIVES: To update and expand the evaluation of the efficacy and safety of relevant treatments for remission induction and maintenance after a mild, moderate or severe flare of UC. RECIPIENTS: Gastroenterologists, coloproctologists, general practitioners, family physicians and others health professionals, interested in the treatment of UC. METHODOLOGY: GADECCU authorities obtained authorization from GETECCU to adapt and update the GETECCU 2020 Guide for the treatment of UC. Prepared with GRADE methodology. A team was formed that included authors, a panel of experts, a nurse and a patient, methodological experts, and external reviewers. GRADE methodology was used with the new information. RESULTS: A 118-page document was prepared with the 44 GADECCU 2022 recommendations, for different clinical situations and therapeutic options, according to levels of evidence. A section was added with the new molecules that are about to be available. CONCLUSIONS: This guideline has been made in order to facilitate decision-making regarding the treatment of UC, adapting and updating the guide prepared by GETECCU in the year 2020.

Evaluation of AIF-1 (Allograft Inflammatory Factor-1) as a Biomarker of Crohn's Disease Severity.

Background: Recently, increased tissue levels of AIF-1 have been shown in experimental colitis, supporting its role in intestinal inflammation. Therefore, we studied the levels of AIF-1 in Crohn's disease (CD). Methods: This study included 33 patients with CD (14 men and 19 women) who participated in the PREDICROHN project, a prospective multicenter study of the Spanish Group of Inflammatory bowel disease (GETECCU). Results: This article demonstrates declines with respect to baseline levels of serum AIF-1 in Crohn's disease (CD) patients after 14 weeks of treatment with anti-TNFs. Furthermore, in patients with active CD (HB ≥ 5), serum AIF-1 levels were significantly higher than those in patients without activity (HB ≤ 4). The study of serum AIF-1 in the same cohort, revealed an area under the ROC curve (AUC) value of AUC = 0.66 (p = 0.014), while for the CRP (C-reactive protein), (AUC) value of 0.69 (p = 0.0066), indicating a similar ability to classify CD patients by their severity. However, the combination of data on serum levels of AIF-1 and CRP improves the predictive ability of these analyses for classifying CD patients as active (HB ≥ 5) or inactive (HB ≤ 4). When we used the odds ratio (OR) formula, we observed that patients with CRP > 5 mg/L or AIF-1 > 200 pg/mL or both conditions were 13 times more likely to show HB ≥ 5 (active CD) than were those with both markers below these thresholds. Conclusion: The development of an algorithm that includes serum levels of AIF-1 and CRP could be useful for assessing Crohn's disease severity.

Risk of Immunomediated Adverse Events and Loss of Response to Infliximab in Elderly Patients with Inflammatory Bowel Disease: A Cohort Study of the ENEIDA Registry.

BACKGROUND AND AIMS: Immunomediated adverse events [IAEs] are the most frequently reported infliximab [IFX]-related adverse events. Combination therapy may reduce their incidence, although this strategy is not recommended in elderly patients. We aimed to compare the rates of IFX-related IAEs and loss of response [LOR] in elderly and younger patients. METHODS: Adult patients in the ENEIDA registry who had received a first course of IFX therapy were identified and grouped into two cohorts regarding age at the beginning of treatment [over 60 years and between 18 and 50 years]. The rates of IAEs and LOR were compared. RESULTS: In total, 939 patients [12%] who started IFX over 60 years of age and 6844 [88%] below 50 years of age were included. Elderly patients presented a higher proportion of AEs related to IFX [23.2% vs 19%; p = 0.002], infections [7.1% vs 4.3%; p < 0.001] and neoplasms [2.2% vs 0.5%; p < 0.001]. In contrast, the rates of IAEs [14.8% vs 14.8%; p = 0.999], infusion reactions [8.1% vs 8.1%; p = 0.989], late hypersensitivity [1.3% vs 1.2%; p = 0.895], paradoxical psoriasis [1% vs 1.5%; p = 0.187] and drug-induced lupus erythematosus [0.6% vs 0.7%; p = 0.947] were similar in elderly and younger patients. LOR rates were also similar between the two groups [20.5% vs 19.3%; p = 0.438]. In the logistic regression analysis, IFX monotherapy, extraintestinal manifestations and female gender were the only risk factors for IAEs, whereas IFX monotherapy, extraintestinal manifestations and Crohn's disease were risk factors for LOR. CONCLUSIONS: Elderly patients with inflammatory bowel disease have a similar risk of developing IFX-related IAEs and LOR to that of younger patients.

Relationship between IGF-1 and body weight in inflammatory bowel diseases: Cellular and molecular mechanisms involved.

Inflammatory bowel diseases (IBD), represented by ulcerative colitis (UC) and Crohn's disease (CD), are characterized by chronic inflammation of the gastrointestinal tract, what leads to diarrhea, malnutrition, and weight loss. Depression of the growth hormone-insulin-like growth factor-1 axis (GH-IGF-1 axis) could be responsible of these symptoms. We demonstrate that long-term treatment (54 weeks) of adult CD patients with adalimumab (ADA) results in a decrease in serum IGF-1 without changes in serum IGF-1 binding protein (IGF1BP4). These results prompted us to conduct a preclinical study to test the efficiency of IGF-1 in the medication for experimental colitis. IGF-1 treatment of rats with DSS-induced colitis has a beneficial effect on the following circulating biochemical parameters: glucose, albumin, and total protein levels. In this experimental group we also observed healthy maintenance of colon size, body weight, and lean mass in comparison with the DSS-only group. Histological analysis revealed restoration of the mucosal barrier with the IGF-1 treatment, which was characterized by healthy quantities of mucin production, structural maintenance of adherers junctions (AJs), recuperation of E-cadherin and ß-catenin levels and decrease in infiltrating immune cells and in metalloproteinase-2 levels. The experimentally induced colitis caused activation of apoptosis markers, including cleaved caspase 3, caspase 8, and PARP and decreases cell-cycle checkpoint activators including phosphorylated Rb, cyclin E, and E2F1. The IGF-1 treatment inhibited cyclin E depletion and partially protects PARP levels. The beneficial effects of IGF-1 in experimental colitis could be explained by a re-sensitization of the IGF-1/IRS-1/AKT cascade to exogenous IGF-1. Given these results, we postulate that IGF-1 treatment of IBD patients could prove to be successful in reducing disease pathology.

Clinical outcome after anti-tumour necrosis factor therapy discontinuation in 1000 patients with inflammatory bowel disease: the EVODIS long-term study.

BACKGROUND: The long-term outcome of patients after antitumour necrosis factor alpha (anti-TNF) discontinuation is not well known. AIMS: To assess the risk of relapse in the long-term after anti-TNF discontinuation. METHODS: This was an extension of the evolution after anti-TNF discontinuation in patients with inflammatory bowel disease (EVODIS) study (Crohn's disease or ulcerative colitis patients treated with anti-TNFs in whom these drugs were withdrawn after achieving clinical remission) based in the same cohort of patients whose outcome was updated. Clinical remission was defined as a Harvey-Bradshaw index ≤4 points in Crohn's disease, a partial Mayo score ≤2 in ulcerative colitis and the absence of fistula drainage despite gentle finger compression in perianal disease. RESULTS: This was an observational, retrospective, multicenter study. A total of 1055 patients were included. The median follow-up time was 34 months. The incidence rate of relapse was 12% per patient-year (95% confidence interval [CI] = 11-14). The cumulative incidence of relapse was 50% (95% CI = 47-53): 19% at one year, 31% at 2 years, 38% at 3 years, 44% at 4 years and 48% at 5 years of follow-up. Of the 60% patients retreated with the same anti-TNF after relapse, 73% regained remission. Of the 75 patients who did not respond, 48% achieved remission with other therapies. Of the 190 patients who started other therapies after relapse, 62% achieved remission with the new treatment. CONCLUSIONS: A significant proportion of patients who discontinued the anti-TNF remained in remission. In case of relapse, retreatment with the same anti-TNF was usually effective. Approximately half of the patients who did not respond after retreatment achieved remission with other therapies.

Effectiveness and Safety of Ustekinumab in Ulcerative Colitis: Real-world Evidence from the ENEIDA Registry.

BACKGROUND AND AIMS: The development programm UNIFI has shown promising results of ustekinumab in ulcerative colitis [UC] treatment which should be confirmed in clinical practice. We aimed to evaluate the durability, effectiveness, and safety of ustekinumab in UC in real life. METHODS: Patients included in the prospectively maintained ENEIDA registry, who received at least one intravenous dose of ustekinumab due to active UC [Partial Mayo Score [PMS]>2], were included. Clinical activity and effectiveness were defined based on PMS. Short-term response was assessed at Week 16. RESULTS: A total of 95 patients were included. At Week 16, 53% of patients had response [including 35% of patients in remission]. In the multivariate analysis, elevated serum C-reactive protein was the only variable significantly associated with lower likelihood of achieving remission. Remission was achieved in 39% and 33% of patients at Weeks 24 and 52, respectively; 36% of patients discontinued the treatment with ustekinumab during a median follow-up of 31 weeks. The probability of maintaining ustekinumab treatment was 87% at Week 16, 63% at Week 56, and 59% at Week 72; primary failure was the main reason for ustekinumab discontinuation. No variable was associated with risk of discontinuation. Three patients reported adverse events; one of them had a fatal severe SARS-CoV-2 infection. CONCLUSIONS: Ustekinumab is effective in both the short and the long term in real life, even in a highly refractory cohort. Higher inflammatory burden at baseline correlated with lower probability of achieving remission. Safety was consistent with the known profile of ustekinumab.

Guía GETECCU 2020 para el tratamiento de la colitis ulcerosa. Elaborada con metodología GRADE / GETECCU 2020 guidelines for the treatment of ulcerative colitis. Developed using the GRADE approach

INTRODUCCIÓN: Desde la publicación de la primera edición de la Guía en 2013, se ha generado mucha información en torno al tratamiento de la colitis ulcerosa, y se han introducido nuevos fármacos y protocolos de actuación. La práctica clínica ha variado substancialmente, lo que justifica nuevas aproximaciones y una revisión exhaustiva, así como la actualización de la evidencia. MATERIAL Y MÉTODOS: Se utiliza nuevamente metodología GRADE, apoyados en una herramienta electrónica (https://gradepro.org). Los escenarios clínicos son los mismos que en la versión previa (inducción y mantenimiento en brote grave y en brote leve-moderado), así como las variables y su evaluación. En la guía actualizada, en relación a la versión previa, se eliminan tres preguntas, se añaden 14 y se mantienen 30, con un total de 44 preguntas clínicas. Tras una exhaustiva revisión de la evidencia, se actualizan las recomendaciones. RESULTADOS: De las 44 preguntas analizadas, en dos de ellas no se ha podido establecer ninguna recomendación por muy baja calidad de la evidencia, mientras que en las 42 restantes, basados en diferentes grados de calidad de evidencia, se ha formulado una recomendación de acuerdo con el sistema GRADE. En 25 de estas preguntas la recomendación final es fuerte a favor; en seis, fuerte en contra; mientras que en siete es débil a favor, y en cuatro débil en contra. Siguiendo los escenarios y las recomendaciones, se proponen seis algoritmos como guía sencilla en la toma de decisiones prácticas. CONCLUSIONES: Esta actualización de la guía previa publicada en 2013 intenta dar respuesta basada en la metodología GRADE a las diferentes preguntas que nos hacemos diariamente a la hora de decidir el tratamiento más adecuado de nuestros pacientes con colitis ulcerosa en los diferentes escenarios clínicos

INTRODUCTION: Since the first edition of the Guidelines was published in 2013, much information has been generated around the treatment of ulcerative colitis, and new drugs and action protocols have been introduced. Clinical practice has changed substantially, warranting new approaches and a comprehensive review and update of the evidence. MATERIAL AND METHODS: Once again, we used the GRADE approach, supported by an electronic tool (https://gradepro.org). The clinical scenarios are the same as in the previous version (induction and maintenance in severe and mild-moderate flare-ups), as are the variables and their evaluation. However, in the updated guidelines, three questions have been deleted, 14 added and 30 maintained, making a total of 44 clinical questions. After an exhaustive review of the evidence, the recommendations are now updated. RESULTS: Of the 44 questions analysed, no recommendation could be established in two due to the very low quality of the evidence, while in the other 42, based on different degrees of quality of evidence, recommendations were made according to the GRADE system. In 25 of these questions the final recommendation is strongly in favour, in six strongly against, in seven weakly in favour and in four weakly against. According to the scenarios and recommendations, six algorithms are proposed as a simple guide for practical decision-making. CONCLUSIONS: The aim of this update of the 2013 guidelines is to provide answers, based on the GRADE approach, to the different questions we ask ourselves daily when deciding the most appropriate treatment for our patients with ulcerative colitis in the different clinical scenarios

GETECCU 2020 guidelines for the treatment of ulcerative colitis. Developed using the GRADE approach. / Guía GETECCU 2020 para el tratamiento de la colitis ulcerosa. Elaborada con metodología GRADE.

INTRODUCTION: Since the first edition of the Guidelines was published in 2013, much information has been generated around the treatment of ulcerative colitis, and new drugs and action protocols have been introduced. Clinical practice has changed substantially, warranting new approaches and a comprehensive review and update of the evidence. MATERIAL AND METHODS: Once again, we used the GRADE approach, supported by an electronic tool (https://gradepro.org). The clinical scenarios are the same as in the previous version (induction and maintenance in severe and mild-moderate flare-ups), as are the variables and their evaluation. However, in the updated guidelines, three questions have been deleted, 14 added and 30 maintained, making a total of 44 clinical questions. After an exhaustive review of the evidence, the recommendations are now updated. RESULTS: Of the 44 questions analysed, no recommendation could be established in two due to the very low quality of the evidence, while in the other 42, based on different degrees of quality of evidence, recommendations were made according to the GRADE system. In 25 of these questions the final recommendation is strongly in favour, in six strongly against, in seven weakly in favour and in four weakly against. According to the scenarios and recommendations, six algorithms are proposed as a simple guide for practical decision-making. CONCLUSIONS: The aim of this update of the 2013 guidelines is to provide answers, based on the GRADE approach, to the different questions we ask ourselves daily when deciding the most appropriate treatment for our patients with ulcerative colitis in the different clinical scenarios.

Real-world long-term effectiveness of ustekinumab in Crohn's disease: results from the ENEIDA registry.

BACKGROUND: Data on the long-term administration of ustekinumab in recommended doses are limited. AIM: To assess the real-world, long-term effectiveness of ustekinumab in refractory Crohn's disease (CD). METHODS: Multi-centre study of CD patients starting ustekinumab at the recommended dose, followed for 1 year. Values for the Harvey-Bradshaw Index (HBI), endoscopic activity, C-reactive protein (CRP), and faecal calprotectin (FC) were recorded at baseline and at weeks 26 and 52. Demographic and clinical data, previous treatments, adverse events (AEs) and hospitalisations were documented. Potential predictors of remission were examined. RESULTS: A total of 407 patients were analysed. The initial maintenance dose of 90 mg SC was administered every 12, 8 and 4 weeks in 56 (14%), 347 (85%) and 4 (1%) patients, respectively. After 52 weeks, treatment was discontinued in 112 patients (27.5%). At baseline, 295 (72%) had an HBI >4 points. Of these, 169 (57%) and 190 (64%) achieved clinical remission at weeks 26 and 52, respectively. FC levels returned to normal in 44% and 54% of patients at weeks 26 and 52, and CRP returned to normal in 36% and 37% of patients at weeks 26 and 52, respectively. AEs were recorded in 60 patients. The use of fewer previous anti-TNFα agents and ileal localisation were associated with clinical remission, and endoscopic severity was associated with poor response. No factors correlated with endoscopic remission. CONCLUSION: After 52 weeks, ustekinumab demonstrated effectiveness in inducing clinical and endoscopic remission in patients with refractory CD.