Rigorous Donor Selection for Fecal Microbiota Transplantation in Active Ulcerative Colitis: Key Lessons From a Randomized Controlled Trial Halted for Futility.

BACKGROUND & AIMS: Rigorous donor preselection on microbiota level, strict anaerobic processing, and repeated fecal microbiota transplantation (FMT) administration were hypothesized to improve FMT induction of remission in ulcerative colitis (UC). METHODS: The RESTORE-UC trial was a multi-centric, double-blind, sham-controlled, randomized trial. Patients with moderate to severe UC (defined by total Mayo 4-10) were randomly allocated to receive 4 anaerobic-prepared allogenic or autologous donor FMTs. Allogenic donor material was selected after a rigorous screening based on microbial cell count, enterotype, and the abundance of specific genera. The primary endpoint was steroid-free clinical remission (total Mayo ≤2, no sub-score >1) at week 8. A pre-planned futility analysis was performed after 66% (n = 72) of intended inclusions (n = 108). Quantitative microbiome profiling (n = 44) was performed at weeks 0 and 8. RESULTS: In total, 72 patients were included, of which 66 received at least 1 FMT (allogenic FMT, n = 30 and autologous FMT, n = 36). At week 8, respectively, 3 and 5 patients reached the primary endpoint of steroid-free clinical remission (P = .72), indicating no treatment difference of at least 5% in favor of allogenic FMT. Hence, the study was stopped due to futility. Microbiome analysis showed numerically more enterotype transitions upon allogenic FMT compared with autologous FMT, and more transitions were observed when patients were treated with a different enterotype than their own at baseline (P = .01). Primary response was associated with lower total Mayo scores, lower bacterial cell counts, and higher Bacteroides 2 prevalence at baseline. CONCLUSION: The RESTORE-UC trial did not meet its primary endpoint of increased steroid-free clinical remission at week 8. Further research should additionally consider patient selection, sterilized sham-control, increased frequency, density, and viability of FMT prior to administration. CLINICALTRIALS: gov, Number: NCT03110289.

Perianal fistulising Crohn's disease: utilising the TOpClass classification in clinical practice to provide targeted individualised care.

BACKGROUND AND AIMS: Perianal fistulation is a challenging phenotype of Crohn's disease with significant impact on quality of life. Historically, fistulae have been classified anatomically in relation to the sphincter complex, and management guidelines have been generalised, with lack of attention to the clinical heterogenicity seen. The recent 'TOpClass classification system' for perianal fistulising Crohn's disease (PFCD) addresses this issue, and classifies patients into defined groups, which provide a focus for fistula management that aligns with disease characteristics and patient goals. In this article, we discuss the clinical applicability of the TOpClass model and provide direction on its use in clinical practice. METHODS: An international group of perianal clinicians participated in an expert consensus to define how the TOpClass system can be incorporated into real-life practice. This included gastroenterologists, IBD surgeons, and radiologists specialised in PFCD. The process was informed by the multi-disciplinary team management of eight high-volume fistula centres in North America, Europe, and Australia. RESULTS: The process produced position statements to accompany the classification system and guide PFCD management. The statements range from the management of patients with quiescent perianal disease to those with severe PFCD requiring diverting-ostomy and/or proctectomy. The optimisation of medical therapies, as well as the use of surgery, in fistula closure and symptom management is explored across each classification group. CONCLUSION: This article provides an overview of the system's use in clinical practice. It aims to enable clinicians to have a pragmatic and patient-goal centred approach to medical and surgical management options for individual patients with PFCD.

Case report and review of literature: IgG4-gastroduodenitis in upper GI Crohn's disease: two separate entities or just a marker of disease severity?

A 20-year-old man was presented with ulcerative gastritis and duodenitis complicated by pyloric stenosis. Helicobacter pylori infection was excluded, and the lesions did not respond to treatment with proton pump inhibitors. No other parts of the intestinal tract showed signs of inflammation. Histopathological review showed signs of chronic inflammation with granuloma formation. A tentative diagnosis of isolated upper gastrointestinal (UGI) Crohn's disease was performed. However, additional work-up revealed significantly positive IgG4 staining as well as elevated IgG4 serum levels. Since granulomatous disease is unlikely in IgG4-related disease, an eventual diagnosis of overlapping IgG4-related disease and Crohn's disease (CD) was performed. Treatment with systemic steroids and anti-TNF in combination with azathioprine led to rapid symptomatic improvement. In this article, we review the available literature on IgG4-related gastroduodenitis, granulomatous gastritis, and upper GI CD. We suggest the possibility that IgG4-infiltration may be a marker of severely active inflammatory bowel disease rather than a separate disease entity.

Unraveling the fatigue puzzle: insights into the pathogenesis and management of IBD-related fatigue including the role of the gut-brain axis.

A significant percentage of patients with an inflammatory bowel disease (IBD) encounter fatigue which can profoundly diminish patients' quality of life, particularly during periods of disease remission when gastrointestinal symptoms have receded. Various contributing risk factors have been identified including active inflammation, anemia, psychological, lifestyle and drug-related factors. While addressing these risk factors has been suggested as the initial approach to managing fatigue, a considerable number of patients still experience persisting symptoms, the primary causes of which remain incompletely understood. Recent insights suggest that dysfunction of the gut-brain axis may play a pathogenic role. This review provides an overview of established risk factors for fatigue, alongside emerging perspectives on the role of the gut-brain axis, and potential treatment strategies.

Safety and Effectiveness of Vedolizumab and Ustekinumab in Elderly Patients with Inflammatory Bowel Disease: A Real-Life Multicentric Cohort Study.

BACKGROUND: Data on ustekinumab and vedolizumab in the elderly inflammatory bowel disease (IBD) population are limited. The aim of the current study was to assess the safety and effectiveness of both in an elderly real-life population. METHODS: A multicentric retrospective study was performed on IBD patients who started vedolizumab or ustekinumab between 2010 and 2020. Clinical and endoscopic remission rates and (serious) adverse events (AE) were assessed. RESULTS: A total of 911 IBD patients were included, with 171 (19%) aged above 60 (111 VDZ, 60 UST). Elderly patients treated with vedolizumab or ustekinumab had an increased risk for non-IBD hospitalization (10.5% vs. 5.7%, p = 0.021) and malignancy (2.3% vs. 0.5%, p = 0.045) compared to the younger population. Corticosteroid-free clinical (50% vs. 44%; p = 0.201) and endoscopic remission rates (47.9% vs. 31%, p = 0.07) at 1 year were similar. Comparing vedolizumab to ustekinumab in the elderly population, corticosteroid-free (47.9% vs. 31%, p = 0.061) and endoscopic remission rates (66.7% vs. 64.4%, p = 0.981) were similar. Vedolizumab- and ustekinumab-treated patients had comparable infection rates (13.5% vs. 10.0%, p = 0.504), IBD flare-ups (4.5% vs. 5%, p = 1.000), the occurrence of new EIMs (13.5% vs. 10%, p = 0.504), a risk of intestinal surgery (5.4% vs. 6.7%, p = 0.742), malignancy (1.8% vs. 3.3%, p = 0.613), hospitalization (9.9% vs. 11.7%, p = 0.721), and mortality (0.9% vs. 1.7%, p = 1.000). AE risk was associated only with corticosteroid use. CONCLUSIONS: Ustekinumab and vedolizumab show comparable effectiveness and safety in the elderly IBD population. Elderly IBD patients have an increased risk for non-IBD hospitalizations and malignancy compared to the younger IBD population, with corticosteroid use as the main risk factor.

Prophylactic Versus Endoscopy-driven Treatment of Crohn's Postoperative Recurrence: A Retrospective, Multicentric, European Study [PORCSE Study].

BACKGROUND AND AIMS: No consensus exists on optimal strategy to prevent postoperative recurrence [POR] after ileocaecal resection [ICR] for Crohn's disease [CD]. We compared early medical prophylaxis versus expectant management with treatment driven by findings at elective endoscopy 6-12 months after ICR. METHODS: A retrospective, multicentric, observational study was performed. CD patients undergoing first ICR were assigned to Cohort 1 if a biologic or immunomodulator was [re]started prophylactically after ICR, or to Cohort 2 if no postoperative prophylaxis was given and treatment was started as reaction to elective endoscopic findings. Primary endpoint was rate of endoscopic POR [Rutgeerts >i1]. Secondary endpoints were severe endoscopic POR [Rutgeerts i3/i4], clinical POR, surgical POR, and treatment burden during follow-up. RESULTS: Of 346 included patients, 47.4% received prophylactic postoperative treatment [proactive/Cohort 1] and 52.6% did not [reactive/Cohort 2]. Endoscopic POR [Rutgeerts >i1] rate was significantly higher in Cohort 2 [41.5% vs 53.8%, OR 1.81, p = 0.039] at endoscopy 6-12 months after surgery. No significant difference in severe endoscopic POR was found [OR 1.29, p = 0.517]. Cohort 2 had significantly higher clinical POR rates [17.7% vs 35.7%, OR 3.05, p = 0.002] and numerically higher surgical recurrence rates [6.7% vs 13.2%, OR 2.59, p = 0.051]. Cox proportional hazards regression analysis showed no significant difference in time to surgical POR of proactive versus expectant/reactive approach [HR 2.50, p = 0.057]. Quasi-Poisson regression revealed a significantly lower treatment burden for immunomodulator use in Cohort 2 [mean ratio 0.53, p = 0.002], but no difference in burden of biologics or combination treatment. CONCLUSIONS: The PORCSE study showed lower rates of endoscopic POR with early postoperative medical treatment compared with expectant management after first ileocaecal resection for Crohn's disease.

A comprehensive metabolite fingerprint of fibrostenosis in patients with Crohn's disease.

Intestinal fibrostenosis in patients with Crohn's disease (CD) is a common and untreatable comorbidity that is notoriously difficult to monitor. We aimed to find metabolites associated with the presence of fibrostenosis in patients with CD using targeted and untargeted metabolomics analyses of serum and primary cell cultures using hyphenated ultra-high performance liquid chromatography high-resolution mass spectrometry. Targeted metabolomics revealed 11 discriminating metabolites in serum, which were enriched within the arginine and proline metabolism pathway. Based on untargeted metabolomics and discriminant analysis, 166 components showed a high predictive value. In addition, human intestinal fibroblasts isolated from stenotic tissue were characterized by differential levels of medium-chain dicarboxylic acids, which are proposed as an energy source through beta-oxidation, when oxidative phosphorylation is insufficient. Another energy providing pathway in such situations is anaerobic glycolysis, a theory supported by increased expression of hexokinase 2 and solute carrier family 16 member 1 in stenotic fibroblasts. Of interest, four (unannotated) metabolic components showed a negative correlation with hexokinase 2 gene expression. Together, this study provides a discriminative metabolic fingerprint in the serum and in intestinal fibroblasts of stenotic and non-stenotic patients with CD suggestive for increased production of building blocks for collagen synthesis and increased glycolysis.

Recomendaciones del Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU) sobre la utilidad de la determinación de calprotectina fecal en la enfermedad inflamatoria intestinal / Recommendations of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis (GETECCU) on the utility of the determination of faecal calprotectin in inflammatory bowel disease

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

The management of inflammatory bowel disease (IBD) is currently based on the objective evaluation of intestinal lesions. It would therefore be interesting to have access to simple and non-invasive tools to monitor IBD activity and to identify the presence of lesions. Faecal calprotectin (FC) is the main cytosolic protein of neutrophils, it is resistant to bacterial degradation and it is stable at room temperature for several days, characteristics that make it suitable for use in clinical practice. It can be used to differentiate between inflammatory and functional processes, it correlates with endoscopic activity, it is associated with clinical and endoscopic response to treatment and it has short-term prognostic value. This paper offers an up-to-date perspective on the information that FC can provide clinicians to aid diagnosis, monitoring and management of IBD

Therapeutic requirements in active ulcerative proctitis: A single-centre study / Requerimientos terapéuticos en el tratamiento de los brotes de la proctitis ulcerosa. Estudio unicéntrico

Background: Ulcerative proctitis (UP) presents distinctive clinical characteristics, outcomes and therapeutic approaches as compared to left-sided and extensive ulcerative colitis (UC). Aim: To describe the current therapeutic requirements and clinical outcomes in patients with active UP. Methods: Retrospective observational study conducted in a referral IBD centre. Patients with UP in follow-up between 1989 and 2014 were included. The clinical characteristics, as well as the different treatments and drug formulations administered to treat flares, were recorded. Results: Out of 687 UC patients, 101 patients (15%) with UP were included. Median follow-up was 8 years (IQR 3-14) and 49% of patients presented disease activity during the study period. Topical mesalazine monotherapy (90%) was the most commonly administered treatment for disease activity (mostly as suppositories), followed by topical steroids (47%) and oral mesalazine (56%) in monotherapy or combination therapy. Only 14% and 16% of patients required oral prednisone and beclomethasone, respectively. Conclusions: In clinical practice, active UP presents mostly favourable outcomes. Mesalazine suppositories are by far the most used treatment for these patients (AU)

Antecedentes: La proctitis ulcerosa (PU) presenta unas características clínicas, evolutivas y terapéuticas distintas con respecto a la colitis ulcerosa izquierda o extensa. Objetivo: Describir los requerimientos terapéuticos y la evolución clínica en pacientes con PU activa. Métodos: Estudio observacional retrospectivo realizado en un centro de referencia en EII, en el que se incluyeron pacientes en seguimiento entre 1989 y 2014 con PU. Se registraron las características clínicas, así como los diferentes tratamientos y galénicas utilizados para tratar el brote de actividad. Resultados: De un total de 687 pacientes con colitis ulcerosa se incluyeron 101 (15%) con PU. La mediana de seguimiento fue de 8 años (RIC 3-14). El 49% de los pacientes presentó actividad de la enfermedad durante el período a estudio. La monoterapia con mesalazina tópica (90%) fue el tratamiento más utilizado para la actividad de la enfermedad (predominantemente en forma de supositorios), seguida de los esteroides tópicos (47%) y la mesalazina oral (56%) en monoterapia o en terapia combinada. Solo el 14 y el 16% de los pacientes requirieron prednisona oral y beclometasona, respectivamente. Conclusiones: En la práctica clínica, los supositorios de mesalazina son el tratamiento más utilizado en pacientes con PU activa, presentando la mayoría de ellos una evolución clínica favorable (AU)

Primoinfección por citomegalovirus en enfermedad inflamatoria intestinal / Cytomegalovirus primoinfection in inflammatory bowel disease

No disponible

Calprotectina fecal en el diagnóstico de enfermedades inflamatorias / Fecal calprotectin in the diagnosis of inflammatory bowel diseases

El diagnóstico de las enfermedades inflamatorias intestinales se ha basado, clásicamente, en la valoración de síntomas digestivos. Su aparición suele resultar en una colonoscopia, cuyo rendimiento es bajo. Asimismo, existe una tendencia creciente en fundamentar el tratamiento de la enfermedad inflamatoria intestinal en datos objetivos, ya que la desaparición de los signos de actividad en la colonoscopia (denominada «curación mucosa») se ha relacionado con una remisión clínica sostenida y una reducción en la tasa de hospitalización y cirugía. En consecuencia, es necesario identificar biomarcadores que permitan seleccionar aquellos pacientes que van a beneficiarse más de una exploración endoscópica. La calprotectina fecal ha sido propuesta como biomarcador de inflamación intestinal. Permite diferenciar la enfermedad inflamatoria intestinal del síndrome de intestino irritable, presenta una mejor correlación con el grado de inflamación que los índices clínicos y marcadores serológicos. Además, podría ser útil para predecir la curación mucosa y el riesgo de recidiva (AU)

The diagnosis of inflammatory bowel diseases has classically been based on assessment of digestive symptoms. The development of these symptoms usually results in colonoscopy, which has a low diagnostic yield. Likewise, there is an increasing tendency to base treatment of inflammatory bowel disease on objective data, since the disappearance of signs of activity on colonoscopy (called «mucosal cure») has been associated with sustained clinical remission and reduced rates of hospitalization and surgery. Consequently, there is a need for biomarkers that would aid the selection of those patients who would derive most benefit from an endoscopic examination. One substance that has been proposed as a biomarker of bowel inflammation is fecal calprotectin. This substance allows inflammatory bowel disease to be distinguished from irritable bowel syndrome and shows a better correlation with the degree of inflammation than clinical indicators and serological markers. In addition, it could also be useful to predict mucosal cure and the risk of recurrence (AU)