Ultrasound assessment of gastrointestinal luminal contents: a narrative review.

Gastro-intestinal ultrasound (GIUS) is a non-invasive and cost-effective tool, widely used as a first-line diagnostic method in patients presenting with abdominal complaints, especially in patients affected by inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis. In this setting, gastro-intestinal ultrasound has been especially used to evaluate the bowel wall features (thickening, stratification, vascularization) and complications related to IBD (fistulas, abscesses). Nevertheless, gastro-intestinal ultrasound can be also used to detect and evaluate the content of several segments of the gut. In fact, there is a growing interest in utilizing GIUS for suspected functional disorders, where assessing intestinal content may play a significant diagnostic role, as well as directing therapy. In our review, we provided a sonographic description of GIUS appearances of bowel content in various pathological and physiological conditions, offering potential applications in clinical practice and providing insights for further research.

Intensified versus standard dose infliximab induction therapy for steroid-refractory acute severe ulcerative colitis (PREDICT-UC): an open-label, multicentre, randomised controlled trial.

BACKGROUND: The optimal dosing strategy for infliximab in steroid-refractory acute severe ulcerative colitis (ASUC) is unknown. We compared intensified and standard dose infliximab rescue strategies and explored maintenance therapies following infliximab induction in ASUC. METHODS: In this open-label, multicentre, randomised controlled trial, patients aged 18 years or older from 13 Australian tertiary hospitals with intravenous steroid-refractory ASUC were randomly assigned (1:2) to receive a first dose of 10 mg/kg infliximab or 5 mg/kg infliximab (randomisation 1). Block randomisation was used and stratified by history of thiopurine exposure and study site, with allocation concealment maintained via computer-generated randomisation. Patients in the 10 mg/kg group (intensified induction strategy [IIS]) received a second dose at day 7 or earlier at the time of non-response; all patients in the 5 mg/kg group were re-randomised between day 3 and day 7 (1:1; randomisation 2) to a standard induction strategy (SIS) or accelerated induction strategy (AIS), resulting in three induction groups. Patients in the SIS group received 5 mg/kg infliximab at weeks 0, 2, and 6, with an extra 5 mg/kg dose between day 3 and day 7 if no response. Patients in the AIS group received 5 mg/kg infliximab at weeks 0, 1, and 3, with the week 1 dose increased to 10 mg/kg and given between day 3 and day 7 if no response. The primary outcome was clinical response by day 7 (reduction in Lichtiger score to <10 with a decrease of ≥3 points from baseline, improvement in rectal bleeding, and decreased stool frequency to ≤4 per day). Secondary endpoints assessed outcomes to day 7 and exploratory outcomes compared induction regimens until month 3. From month 3, maintenance therapy was selected based on treatment experience, with use of thiopurine monotherapy, combination infliximab and thiopurine, or infliximab monotherapy, with follow-up as a cohort study up to month 12. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02770040, and is completed. FINDINGS: Between July 20, 2016, and Sept 24, 2021, 138 patients were randomly assigned (63 [46%] female and 75 [54%] male); 46 received a first dose of 10 mg/kg infliximab and 92 received 5 mg/kg infliximab. After randomisation 1, we observed no significant difference in the proportion of patients who had a clinical response by day 7 between the 10 mg/kg and 5 mg/kg groups (30 [65%] of 46 vs 56 [61%] of 92, p=0·62; risk ratio adjusted for thiopurine treatment history, 1·06 [95% CI 0·94-1·20], p=0·32). We found no significant differences in secondary endpoints including time to clinical response or change in Lichtiger score from baseline to day 7. Two patients who received 10 mg/kg infliximab underwent colectomy in the first 7 days compared with no patients in the 5 mg/kg group (p=0·21). Three serious adverse events occurred in three patients in both the 10 mg/kg group and 5 mg/kg group. After randomisation 2, the proportions of patients with clinical response at day 14 (34 [74%] of 46 in the IIS group, 35 [73%] of 48 in the AIS group, and 30 [68%] of 44 in the SIS group, p=0·81), clinical remission at month 3 (23 [50%], 25 [52%], 21 [48%], p=0·92), steroid-free remission at month 3 (19 [41%], 20 [42%], 18 [41%], p=1·0), endoscopic remission at month 3 (21 [46%], 22 [46%], 21 [48%], p=0·98), and colectomy at month 3 (three [7%] of 45, nine [19%] of 47, five [12%] of 43, p=0·20) were not significantly different between groups. Between day 8 and month 3, the proportion of patients with at least one infectious adverse event possibly related to infliximab was two (4%) of 46 in the IIS group, eight (17%) of 48 in the AIS group, and eight (18%) of 44 in the SIS group (p=0·082). No deaths occurred in the study. INTERPRETATION: Infliximab is a safe and effective rescue therapy in ASUC. In steroid-refractory ASUC, a first dose of 10 mg/kg infliximab was not superior to 5 mg/kg infliximab in achieving clinical response by day 7. Intensified, accelerated, and standard induction regimens did not result in a significant difference in clinical response by day 14 or in remission or colectomy rates by month 3. FUNDING: Australian National Health and Medical Research Council, Gastroenterology Society of Australia, Gandel Philanthropy, Australian Postgraduate Award, Janssen-Cilag.

Reliability of intestinal ultrasound for evaluating Crohn's disease activity using point-of-care and central reading.

BACKGROUND & AIMS: Intestinal ultrasound (IUS) is increasingly used to assess Crohn's disease (CD) activity in clinical practice. However, application in clinical trials has been limited by heterogeneous scoring methods and concerns about reliability. We aimed to determine the inter- and intra-rater reliability of locally- and centrally-read IUS parameters for evaluating CD using prospectively performed scans. METHODS: Twenty-four participants with CD and 6 gastroenterologists participated in a 2-day workshop where each participant underwent 6 IUS scans in total. Eight IUS parameters (bowel wall thickness [BWT], bowel wall stratification [BWS], color Doppler signal [CDS], inflammatory mesenteric fat [i-fat], submucosal prominence, submucosal layer thickness, haustra coli/peristalsis, and affected segment length) and an overall measure of sonographic disease activity were blindly assessed by the 6 local readers and 4 central gastroenterologist-sonographers. Reliability was quantified using intraclass correlation coefficients (ICCs). Institutional review board approval was granted for this study (12938). RESULTS: Five IUS parameters demonstrated at least moderate (ICC >0.41) inter- and intra-rater reliability when local and central reading was performed (BWT, CDS, i-fat, submucosal prominence, and affected segment length). Reliability was generally better with central, in distinction to local, reading. ICCs for BWS and i-fat were highest when evaluated as binary outcomes. Sensitivity analyses demonstrated that IUS parameters are most reliable when evaluated in the worst affected segment. Fair reliability was observed when local readers identified the worst affected segment. CONCLUSIONS: Local and central reading of IUS demonstrated at least moderate inter- and intra-rater reliability for several parameters. This study supports refining existing activity indices and incorporating IUS central reading into clinical trials.

The effect of dietary emulsifiers and thickeners on intestinal barrier function and its response to acute stress in healthy adult humans: A randomised controlled feeding study.

BACKGROUND: Although dietary emulsifiers are implicated in the pathogenesis of Crohn's disease, their effect has not been studied in humans. AIM: To determine the effects of high- and low-emulsifier diets (HED, LED) on intestinal barrier function in healthy subjects in unstressed and acutely stressed states. METHODS: We conducted a single-blinded, cross-over, controlled feeding trial in 22 healthy adults. After recording 7 days of their habitual diet, we randomised participants to HED or LED with ≥3-week washout between diets. On dietary completion, acute stress was induced via intravenous corticotrophin-releasing hormone. We assessed dietary adherence, effects on 2-h urinary lactulose: rhamnose ratio (LRR), serum concentrations of lipopolysaccharide-binding protein, soluble-CD14 and markers of epithelial injury and inflammation. RESULTS: Dietary adherence was excellent. In an unstressed state, median (interquartile range) LRR during HED was 0.030 (0.018-0.042); on LED, this was 0.042 (0.029-0.078; p = 0.04). LPB concentrations were lower on HED than LED (p = 0.026), but no differences were observed for epithelial injury or inflammation. Under acute stress, LRR increased by 89% (-1% to 486%) on HED (p = 0.004), differing (p = 0.001) from 39% (1%-90%) decrease on LED (p = 0.009). Soluble-CD14 also increased (p < 0.001). The LED had a prolonged carry-over effect on suppressing HED-induced changes during stress. Similar changes in LRR and soluble-CD14 were observed when HED was used as the first diet (both p < 0.01). CONCLUSION: High intake of emulsifiers improved barrier function in the unstressed state, but increased intestinal permeability to stress, without evidence of inflammation. A LED was protective of the stress effect.

Development of Novel High and Low Emulsifier Diets Based upon Emulsifier Distribution in the Australian Food Supply for Intervention Studies in Crohn's Disease.

BACKGROUND: The aims of this study were to develop and evaluate a high/low-emulsifier diet and compare emulsifier content with preclinical studies that have associated Crohn's disease with emulsifiers. METHODS: Supermarkets were audited with a seven-day high- (HED) and low-emulsifier diet (LED) meal plan developed. The emulsifier content of food was sought from food manufacturers, compared to acceptable daily intake (ADI), and doses were provided in trials. Nutritional composition analysis was completed. Healthy adults ate these diets for seven days in a randomized single-blinded cross-over feeding study to assess palatability, tolerability, satiety, food variety, dietary adherence, blinding and the ease of following the meal plan via visual analogue scale. RESULTS: A database of 1680 foods was created. There was no difference in nutritional content between the HED and LED, except HED had a higher ultra-processed food content (p < 0.001). The HED contained 41 emulsifiers, with 53% of the products able to be quantified for emulsifiers (2.8 g/d), which did not exceed the ADI, was similar to that in observational studies, and was exceeded by doses used in experimental studies. In ten participants, diets were rated similarly in palatability-HED mean 62 (5% CI 37-86) mm vs. LED 68 (54-82) mm-in tolerability-HED 41 (20-61) mm vs. LED 55 (37-73) mm-and in satiety HED 57 (32-81) mm vs. LED 49 (24-73) mm. The combined diets were easy to follow (82 (67-97) mm) with good variety (65 (47-81)) and excellent adherence. CONCLUSION: Nutritionally well-matched HED and LED were successfully developed, palatable and well tolerated.

Review article: Mechanisms underlying the effectiveness of exclusive enteral nutrition in Crohn's disease.

BACKGROUND: Exclusive enteral nutrition (EEN) induces remission and mucosal healing in patients with Crohn's disease, but the mechanism of action remains unknown. AIM: To outline current understanding of the mechanisms of action of EEN. METHODS: From a comprehensive literature search, published data were critically examined in a narrative review. RESULTS: Multiple potential mechanisms of action have been identified. EEN optimises nutritional status. Differences in gut microbiota in terms of overall diversity and taxonomic community structure are observed between responders and non-responders to EEN. Therapy with EEN alters microbial metabolites (including faecal short-chain fatty acids, amino acids, branched-chain amino acids and sulphide) and faecal pH. Epithelial effects and restoration of barrier function, as well as changes in mucosal cytokine profiles and T-cell subsets are observed in responders to EEN. The impact of inclusion or exclusion of specific dietary components may be of importance, but putative detrimental components are found in many formulas. A major challenge in interpreting these findings is that they often contradict or change in opposite directions to what is considered 'beneficial'. It is difficult to differentiate between the observations following EEN being driven by EEN per se and those associated with resolving inflammation. CONCLUSIONS: The mechanisms of action of EEN are likely to involve a complex interplay between host mucosal immune response and luminal environment, but the identity of key factors remains poorly understood. A better definition of pathogenic factors may aid in developing more targeted dietary treatment and provide insights into the pathogenesis of Crohn's disease.

Pharmacist-Driven Therapeutic Infliximab Monitoring at the Point of Care Using Rapidly Assessed Drug Levels in Patients with Inflammatory Bowel Disease.

BACKGROUND: Therapeutic monitoring of infliximab is limited by the time lag between drug-level measurement and dose adjustment, along with the cost of dose escalation. Strategies for dose reduction in stable patients on maintenance infliximab at supratherapeutic levels are uncertain. This study determined the feasibility of a pharmacist-driven strategy for immediate dose adjustment using a sliding scale at the point of care in stable patients with inflammatory bowel disease on maintenance therapy. METHODS: Adult patients with stable disease undergoing maintenance therapy with infliximab infusions, 5 mg/kg every 8 weeks, were prospectively studied. Trough drug levels were assessed by a rapid assay (and later by ELISA) at all infusions for up to 12 months with immediate but quantitatively small dose adjustment according to a sliding scale targeting a therapeutic range of 3-7 mcg/mL. Disease activity was assessed both clinically and biochemically. RESULTS: The rapid assay and ELISA detected similar infliximab levels, and the strategy added approximately 30 minutes to the duration of infusion events. Only 20% of 48 patients (77% with Crohn disease) had baseline trough infliximab concentrations within the therapeutic range. This value increased 3-fold after 24 and 48 weeks of interventions. One in 2 patients had baseline supratherapeutic levels, and most were brought into the therapeutic range without a discernible impact on disease activity by 1 dose adjustment, but 2 or 3 adjustments were generally needed for 29% of patients with subtherapeutic levels. Overall, drug costs were reduced by 4%. CONCLUSIONS: Immediate dose adjustment after infliximab rapid assay performed by a pharmacist using a sliding scale is a feasible strategy. Supratherapeutic infliximab levels can be safely and quickly brought into the therapeutic range using small dose adjustments without affecting disease activity, offsetting (at least partly) costs associated with dose escalation.

Lessons from an audit of exclusive enteral nutrition in adult inpatients and outpatients with active Crohn's disease: a single-centre experience.

Objective: To evaluate clinical outcomes, patterns of use, tolerance and nutritional outcomes of exclusive enteral nutrition (EEN) in adults with Crohn's disease and to compare initiation in the inpatient compared with ambulatory care setting. Design/method: Adults with Crohn's disease who received EEN at a single centre over 2.5 years were identified and outcomes assessed via examination of patient records. Results: EEN was initiated in 60 patients (23 as an outpatient) who had objective evidence of active disease. Of 49 in whom the goal was induction of remission, 28 completed EEN and 24 achieved clinical remission/response. Twenty-one withdrew prematurely, due to intolerance in 15 and disease factors in 6. Of 11 with a planned intervention, 6 fulfilled the goal of downstaging disease while two were intolerant. Completion of the prescribed therapy was associated with self-reported adherence to EEN and with improvements in disease activity scores and biochemical markers. Malnutrition halved (40% to 20%) and intentional weight loss (median 5.1 kg) was achieved in six obese patients. The major reason for intolerance was the inability to accept total avoidance of non-formula food. There were no differences in any outcomes according to the location of initiation of therapy. Conclusion: Positive outcomes occur in 70% of adult patients with Crohn's disease tolerating EEN and 81% in those who are able to completely adhere to EEN, without compromise of nutritional status. Similar success occurs when initiated as an inpatient or outpatient. Failure to tolerate EEN is the major hurdle to its use.

Nonspecific ileitis: Impact of histopathology and gastrointestinal ultrasound in achieving the diagnosis of Crohn's disease.

Background and Aim: Nonspecific ileitis is inflammation of the ileum without specific diagnostic features. A minority may go on to develop Crohn's disease, but optimal pathways of further investigation have not been established. This study aimed to identify a cohort of patients with nonspecific ileitis and to determine the value of ileal histology and gastrointestinal ultrasound in identifying/excluding Crohn's disease. Patients and Methods: In a retrospective analysis, all patients having nonspecific ileitis at colonoscopy from January 2010 to August 2021 were identified. Clinical associations with those subsequently diagnosed with Crohn's disease were examined with specific reference to ileal histology and gastrointestinal ultrasound. Results: Of 29 638 procedures, 147 patients (0.5%) had nonspecific ileitis. Crohn's disease was subsequently diagnosed in 8 patients (5.4%) at a median of 148 (range 27-603) days after colonoscopy. The presence of chronic inflammation on ileal biopsies was more common in those subsequently diagnosed with Crohn's disease (63% vs 20%; P = 0.0145). On gastrointestinal ultrasound, none of the 26 patients with normal bowel wall thickness (<3 mm) were subsequently diagnosed with Crohn's disease, and repeat ultrasound in 15 patients 1 year later showed no change. Of the nine patients with abnormal sonographic findings, three were diagnostic for Crohn's disease. Repeat ultrasound revealed Crohn's disease in two, while four had resolution of the abnormal findings. Conclusion: Although ileal histology was of limited value in identifying patients with nonspecific ileitis who were subsequently diagnosed with Crohn's disease, gastrointestinal ultrasound was highly informative. Prospective studies are needed to confirm the value of gastrointestinal ultrasound as a diagnostic and monitoring tool in this setting.

Early sonographic response to a new medical therapy is associated with future treatment response or failure in patients with inflammatory bowel disease.

OBJECTIVE: Gastrointestinal ultrasound (GIUS) accurately assesses inflammation and is responsive to changes in inflammatory bowel disease. This study aimed to determine the prognostic utility of sonographic response in the first 14 weeks of a newly-instituted therapy with therapeutic response at 46 weeks and to compare its performance with standard clinical assessment tools. METHODS: Patients with sonographic evidence of inflammation were assessed by GIUS, clinical activity, serum C-reactive protein and faecal calprotectin again 2, 6 and 14 weeks after commencing a new biologic or thiopurine. Treatment failure was defined as undergoing surgery, hospitalisation, escalation of dosage or introduction of new medication over 46-weeks' follow-up. Sonographic response was defined as a decrease in bowel wall thickness and improved vascularity. RESULTS: In 31 patients (median age 49 years, 74% Crohn's disease), sonographic response at 14 weeks [OR 19.3, 95% confidence interval (CI), 3.23-101.10; P = 0.0054] and faecal calprotectin (P = 0.018), but no clinical disease activity or C-reactive protein, were predictive of subsequent treatment response. Sonographic response alone was predictive at week 6 (P = 0.016), but not week 2. 16% reduction in bowel wall thickness at 6 weeks (area-under-the-receiver-operator-curve=0.86; P = 0.002; sensitivity 72%, specificity 90%), with similar performance for 10% at 14 weeks, was associated with treatment response. CONCLUSION: Sonographic response as early as 6 weeks after initiation of a new therapy may accurately predict treatment outcomes over 46 weeks and is superior to other markers used to monitor disease activity.

Cytomegalovirus in inflammatory bowel disease: a clinical approach.

Cytomegalovirus (CMV) infection can be a challenging clinical problem in patients with inflammatory bowel disease (IBD), particularly ulcerative colitis. Clinical presentation is difficult to distinguish from an underlying disease flare. Several diagnostic modalities are now available and when combined can aid clinicians in the identification of patients who are most likely to benefit from antiviral therapy. The aim of this article is to review the available literature and outline a practical approach to the diagnosis and management of CMV in patients with IBD.

Interrater reliability of the assessment of disease activity by gastrointestinal ultrasound in a prospective cohort of patients with inflammatory bowel disease.

OBJECTIVE: Gastrointestinal ultrasound is a radiological investigation for monitoring patients with inflammatory bowel disease. However, the reliability of the findings depends on the reproducibility of results between different operators. Thus, the study aim was to assess the interrater reliability of gastrointestinal ultrasound in individuals with inflammatory bowel disease between gastroenterologists with varying GIUS experience. . METHODS: Patients were prospectively recruited at the commencement of a new medical therapy for a baseline assessment, with a second assessment at the end of treatment induction (3 months). Consecutive, blinded ultrasounds were performed by two operators for every test. Gastrointestinal ultrasound examination included assessment of bowel wall thickness, vascularity, wall stratification assessment, mesenteric hyperechogenicity and lymphadenopathy. RESULTS: Forty-nine patients were recruited (Crohn's n = 27, ulcerative colitis n = 22) with 35 returning for a repeat assessment at 3 months. At baseline, the intraclass coefficient for bowel wall thickness was near perfect (0.882). By bowel segment, the closest correlation was in the terminal ileum and differences in bowel wall thickness were similar by disease subtype. All other ultrasound indices of disease activity demonstrated substantial to near-perfect agreement with Gwet's agreement coefficient: vascularity (0.681), wall stratification (0.685), mesenteric hyperechogenicity (0.841) and lymphadenopathy (0.633). Similar findings were seen at 3 months. CONCLUSION: There is substantial agreement between operators of varying experience in gastrointestinal ultrasound findings in patients with Crohn's disease or ulcerative colitis and this is repeatedly demonstrated over time. Thus, a well-trained operator should be sufficient to assess disease activity in patients with inflammatory bowel disease.

Standardisation of intestinal ultrasound scoring in clinical trials for luminal Crohn's disease.

BACKGROUND: Intestinal ultrasound (IUS) is a valuable tool for assessment of Crohn's disease (CD). However, there is no widely accepted luminal disease activity index. AIMS: To identify appropriate IUS protocols, indices, items, and scoring methods for measurement of luminal CD activity and integration of IUS in CD clinical trials. METHODS: An expert international panel of adult and paediatric gastroenterologists (n = 15) and radiologists (n = 3) rated the appropriateness of 120 statements derived from literature review and expert opinion (scale of 1-9) using modified RAND/UCLA methodology. Median panel scores of 1 to ≤3.5, >3.5 to <6.5 and ≥6.5 to 9 were considered inappropriate, uncertain and appropriate ratings respectively. The statement list and survey results were discussed prior to voting. RESULTS: A total of 91 statements were rated appropriate with agreement after two rounds of voting. Items considered appropriate measures of disease activity were bowel wall thickness (BWT), vascularity, stratification and mesenteric inflammatory fat. There was uncertainty if any of the existing IUS disease activity indices were appropriate for use in CD clinical trials. Appropriate trial applications for IUS included patient recruitment qualification when diseased segments cannot be adequately assessed by ileocolonoscopy and screening for exclusionary complications. At outcome assessment, remission endpoints including BWT and vascularity, with or without mesenteric inflammatory fat, were considered appropriate. Components of an ideal IUS disease activity index were identified based upon panel discussions. CONCLUSIONS: The panel identified appropriate component items and applications of IUS for CD clinical trials. Empiric evidence, and development and validation of an IUS disease activity index are needed.

Early Assessment With Gastrointestinal Ultrasound in Patients Hospitalised for a Flare of Ulcerative Colitis and Predicting the Need for Salvage Therapy: A Pilot Study.

Approximately 30% of patients hospitalised with severe ulcerative colitis do not respond to corticosteroids, but the decision to introduce salvage therapy is delayed to at least the third day of treatment, according to the widely applied Oxford criteria to assess response. This pilot study aimed to determine if gastrointestinal ultrasound performed on admission can predict steroid-refractory disease. In 10 consecutive patients with severe ulcerative colitis, gastrointestinal ultrasound was performed within 24 h of admission. Six patients failed corticosteroids and required infliximab salvage therapy. Colonic bowel wall thickness was a median of 4.6 mm (range 4.2-5.6 mm) in those responding to steroids compared with 6.2 mm (6-7.9 mm) in those requiring salvage therapy (p = 0.009). Any colonic segment with a bowel wall thickness of >6 mm was associated with the need for salvage therapy (p = 0.033). Gastrointestinal ultrasound may provide an early indication of poor corticosteroid response and enable a timelier introduction of salvage therapy in patients with severe ulcerative colitis.

The Role of Epidemiological Evidence from Prospective Population Studies in Shaping Dietary Approaches to Therapy in Crohn's Disease.

SCOPE: The concept that dietary factors are key risk and preventive agents in the development of Crohn's disease (CD), while widely believed and supported by epidemiological evidence, has yet to lead to clear identification of those factors through clinical trials. The aims are to examine the strength of the epidemiological evidence of diet and its association with CD, examine how interpretation of mostly epidemiological data has shaped ideas for potential dietary therapies, and to explore other factors that have driven the design of dietary clinical trials in CD. METHODS: A literature search is performed in PubMed, Medline, EMBASE, and Google Scholar for prospective cohort studies and randomized clinical trials (RCTs) using search terms-"Crohn's disease," "diet," "risk," "remission," "treat," "cohort," "randomised." RESULTS: Only four prospective cohort studies examine the relationship of diet and CD development, but these trials have been largely ignored by dietary RCTs in CD, which have used predominantly exclusion diets in small populations without objective endpoint assessment. Only one demonstrated clinical benefit to intestinal inflammation. CONCLUSION: Investment in large multicenter dietary clinical trials that focus on dietary inclusions with objective endpoint assessment are needed to provide safe, sustainable dietary therapy to patients with CD.

Effects of fiber intake on intestinal pH, transit, and predicted oral mesalamine delivery in patients with ulcerative colitis.

BACKGROUND AND AIM: Limited data are available on the effects of fermentable fiber in altering intestinal pH and transit to predict efficacy-based delivery profiles of pH-dependent mesalamine coatings in ulcerative colitis (UC). This study aimed to examine regional pH and transit after acute changes in fermentable fiber intake in quiescent UC patients and their effects on drug release systems. METHODS: In a randomized, double-blind study, 18 patients with quiescent UC and 10 healthy controls were supplied meals high (13 g) or low (≤ 2 g) in fermentable fiber and subsequently ingested a wireless pH-motility capsule. After a ≥ 3-day washout, they crossed over to the other diet. Measurements of intestinal pH and transit were used to predict drug release for the various pH-dependent coatings. RESULTS: Increasing fermentable fiber intake lowered overall (median 6.2 [6.1-6.7] vs low: 6.9 [range or interquartile range: 6.4-7.4]; P = 0.01) and distal pH (7.8 [7.3-8.1] vs 8.2 [8.0-8.5]; P = 0.04) in controls. In UC patients, only cecal pH was decreased (high: 5.1 [4.8-5.5] vs low: 5.5 [5.3-5.7]; P < 0.01). Colonic transit in the UC cohort varied widely after a low-fiber intake but tended to normalize after the high fermentable fiber intake. Hypothetical coating dissolution profiles were heterogeneous in UC patients, with a multi-matrix delayed release system having the highest likelihood of patients (20-40%) with incomplete dissolution, and predominant small intestinal dissolution predicted for Eudragit L (94% patients) and S (44-69%). CONCLUSIONS: Patients with quiescent UC have abnormalities in intestinal pH and transit in response to acute changes in fermentable fiber intake. These have potentially detrimental effects on predicted luminal release patterns of pH-dependent 5-aminosalicylic acid release systems.

Review article: determination of the therapeutic range for therapeutic drug monitoring of adalimumab and infliximab in patients with inflammatory bowel disease.

BACKGROUND: Clinical application of therapeutic drug monitoring (TDM) to optimise anti-TNF therapies in patients with IBD depends upon target ranges. AIMS: To review methodology used to determine therapeutic ranges and critically compare and contrast its application to infliximab and adalimumab. METHODS: A systematic review was performed, and relevant literature was summarised and critically examined. RESULTS: Upper limits of the therapeutic range are determined by toxicity, a plateau response and cost. Lower limits are determined by optimal concentration on the target of action in vitro and/or in vivo, or by correlation of drug levels with clinical efficacy using area-under-receiver-operator-curve (AUROC) analysis. In 43 studies, there were huge variations in time at which infliximab and adalimumab levels were measured, the end-points used (clinical remission to mucosal healing), the clinical setting (active disease vs maintenance phase) and the reason for TDM (proactive vs reactive). In the maintenance phase for infliximab, lower trough limits 2.8-5.7 µg/mL are reported depending upon end-points used, with consistent AUROC 0.68-0.77. Adalimumab TDM targets are even less consistent with a lower limit 5.9-11.8 µg/mL (AUROC 0.66-0.83) in some studies, but no cut-off can be identified that is significantly associated with outcome in others, related to inherent pharmacokinetic and pharmacodynamic differences, and heterogeneity of study design. CONCLUSIONS: Evidence for exposure-response relationship is stronger for infliximab than adalimumab. Due to heterogeneity in settings for drug level measurements, therapeutic ranges vary. These factors need to be taken into account when interpreting the evidence and extending this to therapeutic strategies for IBD patients.

Genetic and Inflammatory Biomarkers Classify Small Intestine Inflammation in Asymptomatic First-degree Relatives of Patients With Crohn's Disease.

BACKGROUND & AIMS: Relatives of individuals with Crohn's disease (CD) carry CD-associated genetic variants and are often exposed to environmental factors that increase their risk for this disease. We aimed to estimate the utility of genotype, smoking status, family history, and biomarkers can calculate risk in asymptomatic first-degree relatives of patients with CD. METHODS: We recruited 480 healthy first-degree relatives (full siblings, offspring or parents) of patients with CD through the Guy's and St Thomas' NHS Foundation Trust and from members of Crohn's and Colitis, United Kingdom. DNA samples were genotyped using the Immunochip. We calculated a risk score for 454 participants, based on 72 genetic variants associated with CD, family history, and smoking history. Participants were assigned to highest and lowest risk score quartiles. We assessed pre-symptomatic inflammation by capsule endoscopy and measured 22 markers of inflammation in stool and serum samples (reference standard). Two machine-learning classifiers (elastic net and random forest) were used to assess the ability of the risk factors and biomarkers to identify participants with small intestinal inflammation in the same dataset. RESULTS: The machine-learning classifiers identified participants with pre-symptomatic intestinal inflammation: elastic net (area under the curve, 0.80; 95% CI, 0.62-0.98) and random forest (area under the curve, 0.87; 95% CI, 0.75-1.00). The elastic net method identified 3 variables that can be used to calculate odds for intestinal inflammation: combined family history of CD (odds ratio, 1.31), genetic risk score (odds ratio, 1.14), and fecal calprotectin (odds ratio, 1.04). These same 3 variables were among the 5 factors associated with intestinal inflammation in the random forest model. CONCLUSION: Using machine learning classifiers, we found that genetic variants associated with CD, family history, and fecal calprotectin together identify individuals with pre-symptomatic intestinal inflammation who are therefore at risk for CD. A tool for detecting people at risk for CD before they develop symptoms would help identify the individuals most likely to benefit from early intervention.

Systematic Review: Clinical Utility of Gastrointestinal Ultrasound in the Diagnosis, Assessment and Management of Patients With Ulcerative Colitis.

BACKGROUND AND AIMS: Gastrointestinal ultrasound is useful in the assessment of patients with Crohn's disease, but its application in ulcerative colitis [UC] is less well established. Here we systematically review the role of gastrointestinal ultrasound in patients with UC. METHODS: Searches of the PUBMED and EMBASE databases were performed with the following search strategy: [ultrasound OR sonography] AND [intestinal OR bowel] AND [ulcerative colitis OR inflammatory bowel disease]. The final search was performed in August 2019. RESULTS: Of 6769 studies identified in the search with a further two studies found from other sources, 50 studies met the inclusion criteria. Increased bowel wall thickness and detection of increased blood flow by colour Doppler were the most often applied criteria for defining disease activity and distribution. When compared with other reference investigations, gastrointestinal ultrasound accurately determined disease extent, severity and response to medical therapy. While further information can be obtained from haemodynamic measurements of the abdominal vessels and contrast-enhanced ultrasound, their clinical value was uncertain. Likewise, hydrocolonic sonography has few advantages over standard gastrointestinal ultrasound examination. Of several scoring systems proposed, there is disparity between the measures and a general lack of validation. There has been limited application of gastrointestinal ultrasound in acute severe ulcerative colitis with toxic megacolon, and, while performing well in children, normal limits differ from those in adults. CONCLUSION: Current evidence indicates that gastrointestinal ultrasound has utility in the non-invasive assessment of patients with UC. Continued advances in technology with better image resolution, validation of scoring systems and application at the point of care by gastroenterologists are likely to contribute to increased use of gastrointestinal ultrasound in routine clinical practice.