Early Ultrasound Response and Progressive Transmural Remission After Treatment With Ustekinumab in Crohn's Disease.

BACKGROUND & AIMS: In this STARDUST substudy, the effect of ustekinumab on transmural bowel inflammation was assessed in adults with moderate-to-severe Crohn's disease (CD) by using intestinal ultrasound (IUS), a noninvasive imaging procedure. METHODS: STARDUST was an international, multicenter, phase 3b, interventional, randomized controlled trial specifically designed to compare treat-to-target and standard-of-care treatment strategies in ustekinumab-treated CD patients. In this substudy, the most affected bowel segment at baseline by IUS was used for all analyses. Key IUS endpoints (centrally read, parameter-blinded) were IUS response, transmural remission, bowel wall thickness (BWT), blood flow, bowel wall stratification, and inflammatory fat. RESULTS: Seventy-seven patients were evaluated. IUS response could be determined 4 weeks after treatment initiation, with progressive improvement through week 48. IUS response and transmural remission rates at week 48 were 46.3% and 24.1%, respectively. IUS response, transmural remission, BWT, and blood flow normalization rates were more pronounced in the colon and biologic-naive patients. Fair/moderate reliability (κ = 0.21-0.51) was observed between week 4 IUS response and week 48 overall endoscopic response and fecal calprotectin/complete biomarker outcomes. Endoscopy and IUS baseline agreement was >90% in determining the terminal ileum as the most affected bowel segment. IUS response absence at week 4 was associated with no endoscopic response (based on the simplified endoscopic score for Crohn's disease terminal ileum subscore) at week 48 (negative predictive value = 73%). CONCLUSIONS: In this first international, multicenter, interventional study, IUS showed that ustekinumab-treated CD patients achieved progressive IUS response (46.3%) and transmural remission (24.1%) through week 48, with a more robust response in the colon and biologic-naive patients. CLINICALTRIALS: gov number: NCT03107793.

CORE-IBD: A Multidisciplinary International Consensus Initiative to Develop a Core Outcome Set for Randomized Controlled Trials in Inflammatory Bowel Disease.

BACKGROUND & AIMS: End points to determine the efficacy and safety of medical therapies for Crohn's disease (CD) and ulcerative colitis (UC) are evolving. Given the heterogeneity in current outcome measures, harmonizing end points in a core outcome set for randomized controlled trials is a priority for drug development in inflammatory bowel disease. METHODS: Candidate outcome domains and outcome measures were generated from systematic literature reviews and patient engagement surveys and interviews. An iterative Delphi process was conducted to establish consensus: panelists anonymously voted on items using a 9-point Likert scale, and feedback was incorporated between rounds to refine statements. Consensus meetings were held to ratify the outcome domains and core outcome measures. Stakeholders were recruited internationally, and included gastroenterologists, colorectal surgeons, methodologists, and clinical trialists. RESULTS: A total of 235 patients and 53 experts participated. Patient-reported outcomes, quality of life, endoscopy, biomarkers, and safety were considered core domains; histopathology was an additional domain for UC. In CD, there was consensus to use the 2-item patient-reported outcome (ie, abdominal pain and stool frequency), Crohn's Disease Activity Index, Simple Endoscopic Score for Crohn's Disease, C-reactive protein, fecal calprotectin, and co-primary end points of symptomatic remission and endoscopic response. In UC, there was consensus to use the 9-point Mayo Clinic Score, fecal urgency, Robarts Histopathology Index or Geboes Score, fecal calprotectin, and a composite primary end point including both symptomatic and endoscopic remission. Safety outcomes should be reported using the Medical Dictionary for Regulatory Activities. CONCLUSIONS: This multidisciplinary collaboration involving patients and clinical experts has produced the first core outcome set that can be applied to randomized controlled trials of CD and UC.

Recent advances in clinical practice: advances in cross-sectional imaging in inflammatory bowel disease.

Endoscopy remains the reference standard for the diagnosis and assessment of patients with inflammatory bowel disease (IBD), but it has several important limitations. Cross-sectional imaging techniques such as magnetic resonance enterography (MRE) and intestinal ultrasound (IUS) are better tolerated and safer. Moreover, they can examine the entire bowel, even in patients with stenoses and/or severe inflammation. A variety of cross-sectional imaging activity scores strongly correlate with endoscopic measures of mucosal inflammation in the colon and terminal ileum. Unlike endoscopy, cross-sectional techniques allow complete visualisation of the small-bowel and assess for extraintestinal disease, which occurs in nearly half of patients with IBD. Extramural findings may predict outcomes better than endoscopic mucosal assessment, so cross-sectional techniques might help identify more relevant therapeutic targets. Coupled with their high sensitivity, these advantages have made MRE and IUS the primary non-invasive options for diagnosing and monitoring Crohn's disease; they are appropriate first-line investigations, and have become viable alternatives to colonoscopy. This review discusses cross-sectional imaging in IBD in current clinical practice as well as research lines that will define the future role of these techniques.

[Position paper on reporting of intestinal ultrasound findings in patients with inflammatory bowel disease]. / Positionspapier zur Befunderhebung von Darmultraschallbefunden bei chronisch entzündlichen Darmerkrankungen.

BACKGROUND: Intestinal ultrasound is increasingly used for primary diagnosis, detection of complications and monitoring of patients with Crohn's disease and ulcerative colitis. Standardization of reporting is relevant to ensure quality of the methodology and to improve communication between different specialties. The current manuscript describes the features required for optimized reporting of intestinal ultrasound findings in inflammatory bowel disease (IBD). METHODS: An expert consensus panel of gastroenterologists, radiologists, pathologists, paediatric gastroenterologists and surgeons conducted a systematic literature search. In a Delphi- process members of the Kompetenznetz Darmerkrankungen in collaboration with members of the German Society for Radiology (DRG) voted on relevant criteria for reporting of findings in intestinal ultrasound. Based on the voting results statements were agreed by expert consensus. RESULTS: Clinically relevant aspects of intestinal ultrasound (IUS) findings have been defined to optimize reporting and to standardize terminology. Minimal requirements for standardized reporting are suggested. The statements focus on description of disease activity as well as on complications of IBD. Attributes of intestinal inflammation are described and illustrated by exemplary images. CONCLUSION: The current manuscript provides practical recommendations on how to standardize documentation and reporting from intestinal ultrasound findings in patients with IBD.

Emerging treatment options for extraintestinal manifestations in IBD.

Extraintestinal manifestations (EIMs) are frequently observed in IBDs and contribute considerably to morbidity and mortality. They have long been considered a difficult to treat entity due to limited therapy options, but the increasing use of anti-tumour necrosis factors has dramatically changed the therapeutic approach to EIM in recent years. Newly emerging therapies such as JAK inhibitors and anti-interleukin 12/23 will further shape the available armamentarium. Clinicians dealing with EIMs in everyday IBD practice may be puzzled by the numerous available biological agents and small molecules, their efficacy for EIMs and their potential off-label indications. Current guidelines on EIMs in IBD do not include treatment algorithms to help practitioners in the treatment decision-making process. Herein, we summarise knowledge on emerging biological treatment options and small molecules for EIMs, highlight current research gaps, provide therapeutic algorithms for EIM management and shed light on future strategies in the context of IBD-related EIMs.

[Position paper on endoscopic reporting in IBD]. / Positionspapier zur Befunderstellung endoskopischer Untersuchungen bei Patienten mit chronisch-entzündlichen Darmerkrankungen.

The complete and reliable documentation of endoscopic findings make up the crucial foundation for the treatment of patients with inflammatory bowel diseases such as Crohn´s disease and ulcerative colitis. These findings are, on the one hand, a prerequisite for therapeutic decisions and, on the other hand, important as a tool for assessing the response to ongoing treatments. Endoscopic reports should, therefore, be recorded according to standardized criteria to ensure that the findings of different endoscopists can be adequately compared and that changes in the course of the disease can be traced back. In consideration of these necessities, fifteen members of the Imaging Working Group of the German Kompetenznetz Darmerkrankungen have created a position paper proposing a structure and specifications for the documentation of endoscopic exams. In addition to the formal report structure, the recommendations address a large number of attributes of acute and chronic inflammatory alterations as well as endoscopically detectable complications, which are explained in detail and illustrated using exemplary images. In addition, more frequently used endoscopic activity indices are presented and their use in everyday clinical practice is discussed.

Intestinal ultrasound for monitoring therapeutic response in patients with ulcerative colitis: results from the TRUST&UC study.

OBJECTIVE: Prospective evaluation of intestinal ultrasound (IUS) for disease monitoring of patients with ulcerative colitis (UC) in routine medical practice. DESIGN: TRansabdominal Ultrasonography of the bowel in Subjects with IBD To monitor disease activity with UC (TRUST&UC) was a prospective, observational study at 42 German inflammatory bowel disease-specialised centres representing different care levels. Patients with a diagnosis of a proctosigmoiditis, left-sided colitis or pancolitis currently in clinical relapse (defined as Short Clinical Colitis Activity Index ≥5) were enrolled consecutively. Disease activity and vascularisation within the affected bowel wall areas were assessed by duplex/Colour Doppler ultrasonography. RESULTS: At baseline, 88.5% (n=224) of the patients had an increased bowel wall thickness (BWT) in the descending or sigmoid colon. Even within the first 2 weeks of the study, the percentage of patients with an increased BWT in the sigmoid or descending colon decreased significantly (sigmoid colon 89.3%-38.6%; descending colon 83.0%-42.9%; p<0.001 each) and remained low at week 6 and 12 (sigmoid colon 35.4% and 32.0%; descending colon 43.4% and 37.6%; p<0.001 each). Normalisation of BWT and clinical response after 12 weeks of treatment showed a high correlation (90.5% of patients with normalised BWT had symptomatic response vs 9.5% without symptomatic response; p<0.001). CONCLUSIONS: IUS may be preferred in general practice in a point-of-care setting for monitoring the disease course and for assessing short-term treatment response. Our findings give rise to the assumption that monitoring BWT alone has the potential to predict the therapeutic response, which has to be verified in future studies.

Addendum to S3-Guidelines Crohn's disease and ulcerative colitis: Management of Patients with Inflammatory Bowel Disease in the COVID-19 Pandemic - open questions and answers.

The COVID-19 pandemic is a global outbreak of new onset infections with the SARS-CoV-2 virus. To date, more than 3.4 million people have been infected throughout the world. In Germany, approximately 450,000 patients suffer from inflammatory bowel disease; these patients generally require continuous expert care and support. Against the background of a rapidly accumulating knowledge base on SARS-CoV-2, 68 expert authors of the current DGVS guidelines for Crohn's disease and ulcerative colitis took part in a virtual meeting to compile up-to-date, practice-orientated recommendations aimed at improving the care of patients with IBD. These recommendations address the risk of infection, including the risk for specific patient groups, the possible course of the disease, and consequences for pharmacological and surgical therapies of the underlying disease, as well as general measures for infection prevention and adjuvant prophylactic and therapeutic options.

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms.

OBJECTIVE: Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. DESIGN: Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry. RESULTS: We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3×10-10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33). CONCLUSION: In silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.

Distinct Disease Phenotype of Ulcerative Colitis in Patients With Coincident Primary Sclerosing Cholangitis: Evidence From a Large Retrospective Study With Matched Cohorts.

BACKGROUND: Primary sclerosing cholangitis is a classical extraintestinal manifestation in patients with ulcerative colitis. However, the impact of primary sclerosing cholangitis on the disease course is incompletely understood. OBJECTIVE: This study aimed to assess the impact of primary sclerosing cholangitis on disease phenotype and its course in patients with ulcerative colitis. DESIGN: This is a retrospective study with 3:1 matched cohorts. SETTINGS: Tertiary care center's electronic database was used for data analysis from 2000 and 2018. PATIENTS: Of 782 patients with ulcerative colitis, 77 patients who had coincident primary sclerosing cholangitis were included. MAIN OUTCOME MEASURES: The primary outcomes evaluated were disease characteristics including colonic disease activity, temporal change of disease course, colorectal neoplasia, and colectomy rates. RESULTS: Disease activity during acute flares, assessed by the complete Mayo score, was significantly lower in patients with primary sclerosing cholangitis (6.2 vs 7.3; p < 0.001). In addition, disease activity in patients with primary sclerosing cholangitis was decreased, especially within the first 10 years after disease onset, and biological therapy with anti-tumor necrosis factor and anti-integrin agents was commenced less frequently (22% vs 35%; p = 0.043) and later (10-year risk: 17.4% vs 27.8%; p = 0.034). Patients with primary sclerosing cholangitis were younger at colitis diagnosis (23.3 vs 29.3 years; p < 0.001) and had more extensive disease (75% vs 46%; p < 0.001). Colorectal cancer was more frequently detected in patients with coincident primary sclerosing cholangitis (6/77 vs 16/705; p = 0.016). Colectomy rates did not differ between both groups (14.3% vs 14.5%; p = 0.56). In contrast, patients with ulcerative colitis had to undergo surgery more frequently because of therapy-refractant inflammation, whereas surgery due to neoplasia development was increased in patients with coincident primary sclerosing cholangitis (p = 0.013). LIMITATIONS: The study was limited by its retrospective design. CONCLUSION: Patients who have ulcerative colitis with coincident primary sclerosing cholangitis develop a distinct disease course characterized by an earlier disease onset and lower disease activity, but more frequent extensive disease manifestation and higher risk for colorectal cancer. See Video Abstract at http://links.lww.com/DCR/B45. FENOTIPO DE ENFERMEDAD DISTINTIVO DE LA COLITIS ULCERATIVA EN PACIENTES CON COLANGITIS ESCLEROSANTE PRIMARIA CONCOMITANTE: EVIDENCIA DE UN ESTUDIO RETROSPECTIVO GRANDE CON COHORTES EMPAREJADAS: La colangitis esclerosante primaria es una manifestación extraintestinal clásica en pacientes con colitis ulcerativa. Sin embargo, el impacto de la colangitis esclerosante primaria en el curso de la enfermedad no es comprendido completamente.Evaluar el impacto de la colangitis esclerosante primaria en el fenotipo y curso de la enfermedad en pacientes con colitis ulcerativa.Este es un estudio retrospectivo con cohortes emparejadas 3:1.La base de datos electrónica de un centro de atención terciaria se utilizó para el análisis de datos de 2000 a 2018.782 pacientes con colitis ulcerativa, 77 padecían colangitis esclerosante primaria concomitante y fueron incluidos.Se evaluaron las características de la enfermedad, incluida la actividad de enfermedad colónica, el cambio temporal del curso de la enfermedad, la neoplasia colorrectal y las tasas de colectomía.La actividad de la enfermedad durante los brotes agudos, evaluada por la puntuación completa de Mayo, fue significativamente menor en pacientes con colangitis esclerosante primaria (6.2 vs 7.3; p < 0.001). Además, la actividad de la enfermedad en pacientes con colangitis esclerosante primaria se redujo especialmente en los primeros 10 años después del inicio de la enfermedad, y la terapia biológica con agentes anti-TNF y anti-integrina se inició con menos frecuencia (22% vs 35%; p = 0.043) y más tarde (riesgo a 10 años: 17.4% vs 27.8%; p = 0.034). Los pacientes con colangitis esclerosante primaria eran más jóvenes en el momento del diagnóstico de colitis (23.3 vs 29.3 años; p < 0.001) y tenían enfermedad más extensa (75% vs 46%; p < 0.001). El cáncer colorrectal se detectó con mayor frecuencia en pacientes con colangitis esclerosante primaria concomitante (6/77 vs 16/705; p = 0.016). Las tasas de colectomía no fueron diferentes entre ambos grupos (14.3% vs 14.5%; p = 0.56). En contraste, los pacientes con colitis ulcerativa tuvieron que someterse a cirugía con mayor frecuencia debido a inflamación refractaria a la terapia, mientras que el desarrollo de neoplasia se incrementó en pacientes con colangitis esclerosante primaria concomitante (p = 0.013).El estudio estuvo limitado por su diseño retrospectivo.Los pacientes con colitis ulcerativa con colangitis esclerosante primaria concomitante desarrollan un curso de enfermedad distintivo caracterizado por un inicio temprano de la enfermedad y una menor actividad de la enfermedad, pero con manifestación de enfermedad extensa más frecuente y un mayor riesgo de cáncer colorrectal. Vea el resumen en video en http://links.lww.com/DCR/B45.

Gastrointestinal ultrasound in inflammatory bowel disease: an underused resource with potential paradigm-changing application.

Evolution of treatment targets in IBD has increased the need for objective monitoring of disease activity to guide therapeutic strategy. Although mucosal healing is the current target of therapy in IBD, endoscopy is invasive, expensive and unappealing to patients. GI ultrasound (GIUS) represents a non-invasive modality to assess disease activity in IBD. It is accurate, cost-effective and reproducible. GIUS can be performed at the point of care without specific patient preparation so as to facilitate clinical decision-making. As compared with ileocolonoscopy and other imaging modalities (CT and MRI), GIUS is accurate in diagnosing IBD, detecting complications of disease including fistulae, strictures and abscesses, monitoring disease activity and detecting postoperative disease recurrence. International groups increasingly recognise GIUS as a valuable tool with paradigm-changing application in the management of IBD; however, uptake outside parts of continental Europe has been slow and GIUS is underused in many countries. The aim of this review is to present a pragmatic guide to the positioning of GIUS in IBD clinical practice, providing evidence for use, algorithms for integration into practice, training pathways and a strategic implementation framework.

Treatment of Complicated Anal Fistula by an Endofistular Polyurethane-Sponge Vacuum Therapy: A Pilot Study.

BACKGROUND: Treatment of supra- and transsphincteric anal fistulas remains a clinical challenge because current treatment results are variable and potentially endanger sphincter function. OBJECTIVE: Based on positive results of endoluminal polyurethane-sponge vacuum therapy in the upper and lower GI tract, a new system for endofistular vacuum therapy was developed for anal fistulas to utilize vacuum therapy to remove the endofistular pseudoepithelium and to induce granulation in the fistula tract. DESIGN: This study is based on a prospective case series. PATIENTS: Seven patients with complicated anal fistulas (3 associated with Crohn's disease and 4 of cryptoglandular origin) longer than 4 cm were treated. Initially, the fistula was curettaged and the first endofistular vacuum therapy sponge was positioned in the fistula tract. The inner fistula opening was closed by suture. A 125 mm Hg constant vacuum was applied to the sponge, and the endofistular vacuum therapy sponge was changed a median of 3 (3-5) times after each 48 to 72 hours of constant vacuum therapy. After final removal, the fistulas were reevaluated every other week for 3 months. MAIN OUTCOME MEASURE: The main outcome measured was the closure of the fistula. RESULTS: All patients tolerated the therapy well and no adverse events were observed. Fistula tract closure was demonstrated within 4 weeks after the termination of vacuum therapy. One patient with cryptoglandular fistula developed a recurrence within the follow-up of 3 months. LIMITATIONS: This was an observational study that had no control arm. CONCLUSION: In this pilot case series, the results are encouraging. Because endoluminal vacuum therapy would be a new and sphincter-sparing therapy, this concept warrants further investigation in controlled trials.

Use of Intestinal Ultrasound to Monitor Crohn's Disease Activity.

BACKGROUND & AIMS: We performed a multicenter study to determine whether transabdominal bowel wall ultrasonography, a noninvasive procedure that does not require radiation, can be used to monitor progression of Crohn's disease (CD). METHODS: We performed a 12-month prospective, noninterventional study at 47 sites in Germany, from December 2010 through September 2014. Our study included 234 adult patients with CD who experienced a flare, defined as Harvey-Bradshaw index score of ≥7. All patients received treatment intensification, most with tumor necrosis factor antagonists. Ultrasound parameters and clinical data were assessed at baseline and then after 3, 6, and 12 months. The primary endpoint was the change in ultrasound parameters within 12 months of study enrollment. RESULTS: All patients included had bowel wall alterations either within the terminal ileum and/or segments of the colon. After 3 and 12 months, ultrasonographic examination showed significant improvements of nearly all ultrasound parameters, including reductions in bowel wall thickening or stratification, decreased fibrofatty proliferation, and increased signals in color Doppler ultrasound (P < .01 for all parameters at months 3 and 12). Median Harvey-Bradshaw index scores decreased from 10 at baseline to 2 after 12 months. Improvement in bowel wall thickness correlated with reduced levels of C-reactive protein after 3 months (P ≤ .001). CONCLUSIONS: In a multicenter prospective study, we found that ultrasonographic examination can be used to monitor disease activity in patients with active CD. Bowel ultrasonography seems to be an ideal follow-up method to evaluate early transmural changes in disease activity, in response to medical treatment. German Clinical Trials Register: drks.de/DRKS00010805.

Ascariasis imaging: pictorial essay.

Ascariasis is not widespread in Europe, and the knowledge on how to diagnose and treat the disease is limited to some specialists. On the other hand, clinicians are facing an increasing number of immigrants from high-prevalence countries and are, therefore, challenged to update in this field of infectious diseases. Here we present current knowledge on this infection in 2 parts. The first part discusses clinical features and hot topics in ascariasis, and the second part presents imaging features of ascariasis as a pictorial essay.