Evaluating the pharmacokinetics of upadacitinib for the treatment of moderate-to-severe Crohn's disease.

INTRODUCTION: Janus kinases (JAK) are enzymes involved in signaling pathways that activate the immune system. Upadacitinib, an oral small molecule, is the first JAK inhibitor approved by FDA and EMA for the treatment of moderately to severely active Crohn's disease (CD), following successful phase II and III trials. Compared to other JAK inhibitors, upadacitinib has a high selectivity toward JAK1. This characteristic could improve its efficacy and safety. AREAS COVERED: This review provides an overview of the available knowledge on the pharmacokinetics of upadacitinib as induction and maintenance therapy for CD. EXPERT OPINION: The approval of newer targeted small molecules drug, including JAK inhibitors, marked a significant advancement in terms of effectiveness. In fact, the oral administration, the rapid absorption, the excellent bioavailability and the short serum time of maximum concentration are some of the advantages compared to biologics. The selective inhibition of JAK1 by upadacitinib allows for high efficacy while maintaining a reliable safety profile.

Positioning risankizumab in the treatment algorithm of moderate-to-severe Crohn's disease.

Risankizumab is a humanized monoclonal antibody that inhibits the p19 subunit of IL-23 cytokine. Recently it has been approved for the treatment of patients with moderate-to-severe Crohn's disease (CD). We conducted a scoping review to summarize the available data on risankizumab and to define its positioning in the treatment algorithm of CD. Pubmed, Embase and Scopus databases were searched up to Oct 31, 2023 to identify studies reporting efficacy and safety data of risankizumab in patients with CD. Risankizumab is an effective and safe drug for the management of patients with moderate-to-severe CD. It could be used as first-line therapy in biologic-naive patients and in patients who have previously failed other biological therapies.

When we eat the food is processed and absorbed by the gastrointestinal tract. Sometimes, in some people, the gastrointestinal tract gets inflamed, causing problems like tummy ache and diarrhea: this condition is called Crohn's disease. To help turn off this inflammation and make people with Crohn's disease feel better, there's a new treatment called risankizumab. Risankizumab binds to the proteins in the body that cause inflammation and blocks their effects. This helps to reduce gastrointestinal inflammation and relieve its symptoms. Scientific studies have shown that is effective, safe, and it starts working quickly. Patients using this treatment do not have to go to the hospital every time. After three times in the outpatient's clinic, they can continue the treatment comfortably at home using a small device that sticks to the body and administers the medicine.

Ultrasound remission after biologic induction and long-term endoscopic remission in Crohn's disease: a prospective cohort study.

Background: The Bowel Ultrasound Score (BUSS) accurately detects therapy-related changes by using the Simple Endoscopic Score for Crohn's disease (SES-CD) as the reference standard. We aimed to evaluate ultrasound remission as a treatment target and its prediction for long-term endoscopic remission. Methods: This single-centre prospective observational study, based at a tertiary referral centre in Milan, Italy, enrolled, between March 1, 2018, and January 31, 2021, adult patients with active CD (SES-CD >2) who were starting biologics. Colonoscopy and IUS was performed at baseline and at 12 months (mean 12.8 ± 4.2). The primary outcome was the predictive value of ultrasound remission at week 12 (BUSS ≤3.52) for long-term endoscopic remission at 12 months. The International Bowel Ultrasound Segmental Activity Score (IBUS-SAS) was also calculated and optimal cut-point to detect endoscopic remission was identified through ROC analysis. Findings: 93 patients with CD were included. Of these, 22 patients (24%) achieved endoscopic remission. Week 12 ultrasound remission predicted endoscopic remission (59% compared with 41% of the patients who were not in ultrasound remission; OR 9.93, 95% CI 3.10-31.80; p < 0.001), while week 12 calprotectin values (<50, <100, <250 µg/g) did not. Week 12 ultrasound activity was associated with failure to achieve long-term endoscopic remission (NPV 87%, PPV 54%). IBUS-SAS cut-off to discriminate endoscopic remission was 22.8 (AUC 0.906). ROC curve comparison showed no-significant difference between BUSS and IBUS-SAS (p = 0.46) for detecting endoscopic remission. Interpretation: Early ultrasound remission predicts long-term endoscopic remission, making it a valuable early treatment target for clinical practice and in clinical trials. Larger multicentre validation studies are warranted to confirm these findings. Funding: None.

Accuracy of Information given by ChatGPT for patients with Inflammatory Bowel Disease in relation to ECCO Guidelines.

INTRODUCTION: As acceptance of AI platforms increases, more patients will consider these tools as sources of information. The ChatGPT architecture utilizes a neural network to process natural language, thus generating responses based on the context of input text. The accuracy and completeness of ChatGPT3.5 in the context of Inflammatory Bowel Disease remains unclear. METHODS: In this prospective study, 38 questions worded by IBD patients were inputted into ChatGPT3.5. The following topics were covered: 1) CD, UC and malignancy, 2) maternal medicine 3) infection and vaccination 4) complementary medicine. Responses given by Chat GPT were assessed for accuracy (1 - completely incorrect to 5 - completely correct) and completeness (3-point Likert scale; range 1 - incomplete to 3 - complete) by 14 expert gastroenterologists, in comparison with relevant ECCO guidelines. RESULTS: In terms of accuracy, most replies (84.2%) had a median score of ≥4 (IQR:2) and a mean score of 3.87 (SD: +/- 0.6). For completeness, 34.2% of the replies had a median score of 3 and 55.3 % had a median score of between 2 and <3. Overall, the mean rating was 2.24 (SD: +/- 0.4, Median:2 IQR :1). Though group 3 and 4 had a higher mean for both accuracy and completeness, there was no significant scoring variation between the 4 question groups (Kruskal-Wallis test p:>0.05). However, statistical analysis for the different individual questions revealed a significant difference both for accuracy (p<0.001) and completeness (p<0.001). The questions which rated the highest for both accuracy and completeness were related to smoking, while the lowest rating was related to screening for malignancy and vaccinations especially in the context of immunosuppression and family planning. CONCLUSION: This is the first study to demonstrate the capability of an AI-based system to provide accurate and comprehensive answers to real-world patient queries in IBD. AI systems may serve as a useful adjunct for patients, in addition to standard of care in clinic and validated patient information resources. However, responses in specialist areas may deviate from evidence-based guidance and the replies need to give more firm advice.

Gut Microbiota Metabolites: Unveiling Their Role in Inflammatory Bowel Diseases and Fibrosis.

In recent years, there has been a growing focus on the intricate interplay between the gut microbiota and host health, specifically in the context of inflammatory bowel diseases (IBDs). The gut microbiota produces a diverse array of metabolites, influencing the host's immune response and tissue homeostasis. Noteworthy metabolites, such as short-chain fatty acids, bile acids, and indoles, exert significant effects on intestinal inflammation and fibrosis. This review integrates current research findings to clarify the mechanisms through which gut microbiota metabolites contribute to the progression of IBD and fibrosis, offering insights into potential therapeutic targets and strategies for managing these intricate gastrointestinal conditions. The unraveling of the complex relationship between gut microbiota metabolites and inflammatory processes holds promise for the development of targeted interventions that could lead to more effective and personalized treatment approaches for individuals affected by IBD and subsequent intestinal fibrosis.

Comparison between tofacitinib and ustekinumab as a third-line therapy in refractory ulcerative colitis: A multicenter international study.

BACKGROUND: Ustekinumab and tofacitinib have recently been approved for the management of moderate to severe ulcerative colitis (UC). However, there is no evidence on how they should be positioned in the therapeutic algorithm. The aim of this study was to compare tofacitinib and ustekinumab as third-line therapies in UC patients in whom anti-TNF and vedolizumab had failed. METHODS: This was a multicenter retrospective observational study. The primary outcome was disease progression, defined as the need for steroids, therapy escalation, UC-related hospitalization and/or surgery. Secondary outcomes were clinical remission, normalization of C-reactive protein, endoscopic remission, treatment withdrawal, and adverse events. RESULTS: One-hundred seventeen UC patients were included in the study and followed for a median time of 11.6 months (q1 -q3, 5.5-18.7). Overall, 65% of patients were treated with tofacitinib and 35% with ustekinumab. In the entire study cohort, 63 patients (54%) had disease progression during the follow-up period. Treatment with ustekinumab predicted increased risk of disease progression compared to treatment with tofacitinib in Cox regression analysis (HR: 1.93 [95% CI: 1.06-3.50] p = 0.030). Twenty-eight (68%) patients in the ustekinumab group and 35 (46%) in the tofacitinib group had disease progression over the follow-up period (log-rank test, p < 0.054). No significant differences were observed for the secondary outcomes. Six and 22 adverse events occurred in the ustekinumab and tofacitinib groups, respectively (15% vs. 31%, p = 0.11). CONCLUSIONS: Tofacitinib was more efficacious in reducing disease progression than ustekinumab in this cohort of refractory UC patients. However, prospective head-to-head clinical trials are needed as to confirm these data.

The gut-brain axis: Correlation of choroid plexus volume and permeability with inflammatory biomarkers in Crohn's disease.

BACKGROUND: The dysregulation of the gut-brain axis in chronic inflammatory bowel diseases can cause neuro-psychological disturbances, but the underlying mechanisms are still not fully understood. The choroid plexus (CP) maintains brain homeostasis and nourishment through the secretion and clearance of cerebrospinal fluid. Recent research has demonstrated the existence of a CP vascular barrier in mice which is modulated during intestinal inflammation. This study investigates possible correlations between CP modifications and inflammatory activity in patients with Crohn's disease (CD). METHODS: In this prospective study, 17 patients with CD underwent concomitant abdominal and brain 3 T MRI. The volume and permeability of CP were compared with levels of C-reactive protein (CRP), fecal calprotectin (FC), sMARIA and SES-CD scores. RESULTS: The CP volume was negatively correlated with CRP levels (R = -0.643, p-value = 0.024) and FC (R = -0.571, p-value = 0.050). DCE metrics normalized by CP volume were positively correlated with CRP (K-trans: R = 0.587, p-value = 0.045; Vp: R = 0.706, p-value = 0.010; T1: R = 0.699, p-value = 0.011), and FC (Vp: R = 0.606, p-value = 0.037). CONCLUSIONS: Inflammatory activity in patients with CD is associated with changes in CP volume and permeability, thus supporting the hypothesis that intestinal inflammation could affect the brain through the modulation of CP vascular barrier also in humans.

Superior predictive value of transmural over endoscopic severity for colectomy risk in ulcerative colitis: a multicentre prospective cohort study.

BACKGROUND AND AIMS: Endoscopic activity is associated with an increased risk of surgery in patients with ulcerative colitis [UC]. Transmural activity, as defined by Milan Ultrasound Criteria [MUC] > 6.2, reliably detects endoscopic activity in patients with UC. The present study aimed to assess in UC patients whether transmural severity is a better predictor of colectomy as compared to endoscopy. METHODS: Consecutive adult UC patients were recruited in two IBD Referral Centres and underwent colonoscopy and intestinal ultrasound in a blinded fashion. The need for colectomy was assessed at follow-up. Univariable and multivariable logistic and Cox regression analyses were performed. Receiver operating characteristic [ROC] analysis was used to compare MUC baseline values and Mayo Endoscopic Scores [MES] in predicting colectomy risk. RESULTS: Overall, 141 patients were enrolled, and 13 underwent colectomy in the follow-up period. Both MES (hazard ratio [HR]: 3.15, 95% confidence interval [CI]: 1.18-8.37, p = 0.02) and MUC [HR: 1.48, 95% CI: 1.19-1.76, p < 0.001] were associated with colectomy risk, but only MUC was independently associated with this event on multivariable analysis [HR: 1.46, 95% CI: 1.06-2.02, p = 0.02]. MUC was the only independent variable associated with colectomy risk in patients with clinically active disease (odds ratio [OR]: 1.53 [1.03-2.27], p = 0.03). MUC demonstrated higher accuracy than MES (area under ROC curve [AUROC] 0.83, 95% CI: 0.75-0.92 vs 0.71, 95% CI: 0.62-0.80) and better performance for predicting colectomy [p = 0.02]. The optimal MUC score cut-off value for predicting colectomy, as assessed by the Youden index, was 7.7. CONCLUSIONS: A superior predictive value was found for transmural vs endoscopic severity for colectomy risk in UC patients.

The role of filgotinib in ulcerative colitis and Crohn's disease.

Filgotinib is an oral small molecule that selectively inhibits JAK1. It is already approved for the treatment of moderately to severely active ulcerative colitis (UC). Ongoing studies are evaluating the efficacy and safety of filgotinib in Crohn's disease (CD). The purpose of this review is to summarize the available data regarding filgotinib in the management of UC and CD. We used Pubmed, Embase and clinicaltrials.gov websites to search all available data and currently ongoing studies regarding the efficacy and safety of filgotinib in inflammatory bowel diseases. Filgotinib is an effective and safe drug for the management of biologic-naive and biologic-experienced patients with moderate-to-severe UC. The same efficacy results have not been achieved in CD.

Filgotinib is an oral medication that inhibits the activity of the JAK1 enzyme. It has received approval from the European Medicines Agency for the treatment of moderate-to-severe ulcerative colitis, a condition characterized by inflammation in the lower part of the digestive tract. Filgotinib has a rapid mechanism of action and is effective at relieving the symptoms of ulcerative colitis and maintaining this improvement. However, its use is recommended with caution in patients who have risk factors such as heart and blood vessel issues, active smoking, a history of cancer, or those who are elderly (over 65 years old), and only when there are no other viable treatment options available. Although filgotinib was also studied for managing moderate-to-severe Crohn's disease, a chronic inflammatory condition affecting the digestive system, it did not pass phase III clinical trials and will not be available for this indication.

Role of artificial intelligence in imaging and endoscopy for the diagnosis, monitoring and prognostication of inflammatory bowel disease: a scoping review protocol.

INTRODUCTION: Inflammatory bowel diseases (IBD) are immune-mediated conditions that are increasing in incidence and prevalence worldwide. Their assessment and monitoring are becoming increasingly important, though complex. The best disease control is achieved through tight monitoring of objective inflammatory parameters (such as serum and stool inflammatory markers), cross-sectional imaging and endoscopic assessment. Considering the complexity of the information obtained throughout a patient's journey, artificial intelligence (AI) provides an ideal adjunct to existing tools to help diagnose, monitor and predict the course of disease of patients with IBD. Therefore, we propose a scoping review assessing AI's role in diagnosis, monitoring and prognostication tools in patients with IBD. We aim to detect gaps in the literature and address them in future research endeavours. METHODS AND ANALYSIS: We will search electronic databases, including Medline, Embase, Cochrane CENTRAL, CINAHL Complete, Web of Science and IEEE Xplore. Two reviewers will independently screen the abstracts and titles first and then perform the full-text review. A third reviewer will resolve any conflict. We will include both observational studies and clinical trials. Study characteristics will be extracted using a data extraction form. The extracted data will be summarised in a tabular format, following the imaging modality theme and the study outcome assessed. The results will have an accompanying narrative review. ETHICS AND DISSEMINATION: Considering the nature of the project, ethical review by an institutional review board is not required. The data will be presented at academic conferences, and the final product will be published in a peer-reviewed journal.

Treat-to-Target and Regular Surveillance of Inflammatory Bowel Disease Are Associated with Low Incidence and Early-Stage Detection of Malignancies: A Retrospective Cohort Study.

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), increase the risk of malignancies, particularly colorectal cancer (CRC). We aimed to assess the incidence of malignancies in IBD patients managed using a treat-to-target approach and recommended surveillance. We retrospectively searched the electronic databases of two tertiary IBD centers in Milan from 2010 to 2019 for new diagnoses of malignancy in patients with pre-existing IBD. A total of 5239 patients with a follow-up of 19,820 years were included. In total, 71 malignancies were diagnosed in 70 patients (38 CD, 32 UC) with a mean age of 52.9 years, of whom 64% were former or active smokers. The annual incidence of all malignancies was 358 per 100,000 patient years (95% CI 275-444), and the standardized incidence rate (SIR) was 0.93 (95% CI 0.73-1.16). Gastrointestinal cancers were the most frequent (n = 17, 23.9%), in particular, CRC (n = 9), with an incidence of 45 per 100,000 (95% CI 15-74) and an SIR of 1.18 (95% CI 0.54-2.09). CRC occurred mainly in UC patients (6/8), while small bowel cancer was seen in CD patients (5/9). Melanoma and breast cancer (n = 8 each) were the most common non-GI cancers. No significant difference in incidence was found between CD or UC. Death occurred in nine patients (11%) and was due to cancer in eight of these cases, two of which were IBD-related. Most malignancies included in the surveillance were diagnosed at early (I-II) stages (20 vs. 4, p < 0.05). In patients with IBD, treat-to-target and strict surveillance were associated with a low incidence of cancer, similar to that of the general population, and the detection of malignancies at an early stage.

Leaving behind the Mucosa: Advances and Future Directions of Intestinal Ultrasound in Ulcerative Colitis.

Inflammatory Bowel Diseases (IBD), mainly Ulcerative Colitis (UC) and Crohn's Disease (CD), are disorders characterized by chronic inflammation with severe morbidity and long-term disabling quality of life outcomes. UC mainly affects the mucosal and sub-mucosal layers of the colon, without embracing the peri-intestinal structures. Considering the predominant mucosal location of UC inflammation, the implementation of transmural evaluation by cross-sectional imaging techniques, mainly Intestinal Ultrasound (IUS), has been left behind for ages, especially if compared to CD. Nevertheless, studies analyzing intestinal ultrasound parameters accuracy in disease activity detection reported a good-to-optimal correlation of IUS markers with colonic inflammation, suggesting comparable feasibility of IUS monitoring in UC as in CD. The easy-to-use, costless and point-of-care available status of IUS is therefore crucial in order to improve the diagnostic process and, according to the recent literature, to monitor the response to treatment leading to speeding up decision making and therapy adjustments. Recent studies have demonstrated the correlation between transmural healing in UC with favorable outcomes even in the long term. An evidence gap still exists in the assessment of the rectum, with trans-perineal ultrasound (TPUS) a potential answer to reach a more precise evaluation of rectal inflammation. Eventually, IUS is also increasingly showing promises in emergent or post-surgical UC settings, considering various efforts put in line to demonstrate its feasibility in predicting response to salvage therapy for surgery avoidance and in studying inflammation relapse after procto-colectomy with ileo-pouch-anal anastomosis (IPAA) creation.

Recent advances in the use of ultrasound in Crohn's disease.

INTRODUCTION: A clear consensus exists on the role of IUS for the assessment and monitoring of Crohn's disease (CD) in the 'treat-to-target' strategy. AREAS COVERED: IUS is an accurate tool for the management of CD. It is noninvasive and well tolerated. IUS has good-to-optimal inter-operator reliability either for assessing disease activity or for evaluating treatment response, especially combining Bowel Wall Thickness (BWT) and Color Doppler Signals (CDS). IUS is able to evaluate transmural remission (TR), the ultimate goal of the 'treat-to-target' strategy. Several studies confirmed its accuracy in the assessment of the post-operative recurrence (POR). Thanks to recent advances in trans-perineal ultrasound technique (TPUS), it allows to characterize peri-anal disease and its complications. Small intestine contrast ultrasound (SICUS) and contrast-enhancement ultrasound (CEUS) may improve IUS performance, particularly in stricturing or penetrating CD. Ultrasound elastography (USE) is raising interest for its accuracy in differentiating CD phenotypes (fibrotic versus inflamed). EXPERT OPINION: IUS is a pivotal step in the management of CD, in early assessment as in therapeutic monitoring, with advantages of evaluating transmural response. Development and validation of novel ultrasound biomarkers of activity and fibrosis, especially those linked to advanced ultrasound techniques, are expected in the coming years.

The Earlier You Find, the Better You Treat: Red Flags for Early Diagnosis of Inflammatory Bowel Disease.

Delayed diagnosis is a challenge in the management of inflammatory bowel disease (IBD). Several studies show a significant association between diagnostic delay and disease progression to complications and surgery, especially in Crohn's disease (CD). What risk factors are associated with diagnostic delay in IBD remains unclear. In order to reduce diagnostic delay, the Red Flags Index has been developed and validated. The combination of the Red Flags Index score and non-invasive biomarkers such as fecal calprotectin seems to be highly accurate in screening patients with underlying IBD to be referred for further diagnostic workup and eventual early effective treatment strategies. Our literature review aims to obtain a comprehensive overview of the impacts of diagnostic delay in IBD on the potential risk factors associated with IBD, how diagnostic tools may be effective in reducing diagnostic delay, and future perspectives in this field.

New Technologies in Digestive Endoscopy for Ulcerative Colitis Patients.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease primarily affecting the colon and rectum. Endoscopy plays a crucial role in the diagnosis and management of UC. Recent advancements in endoscopic technology, including chromoendoscopy, confocal laser endomicroscopy, endocytoscopy and the use of artificial intelligence, have revolutionized the assessment and treatment of UC patients. These innovative techniques enable early detection of dysplasia and cancer, more precise characterization of disease extent and severity and more targeted biopsies, leading to improved diagnosis and disease monitoring. Furthermore, these advancements have significant implications for therapeutic decision making, empowering clinicians to carefully consider a range of treatment options, including pharmacological therapies, endoscopic interventions and surgical approaches. In this review, we provide an overview of the latest endoscopic technologies and their applications for diagnosing and monitoring UC. We also discuss their impact on treatment decision making, highlighting the potential benefits and limitations of each technique.

Efficacy and Safety of S1P1 Receptor Modulator Drugs for Patients with Moderate-to-Severe Ulcerative Colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) that negatively impacts patients' quality of life. In the last decades, the therapeutic options available for the management of patients with moderate to severe UC have increased significantly, including not only biological drugs but also small molecules. However, there is a persistent need to develop new drugs that act on new targets while minimizing the risk of adverse events. Sphingosine-1-phosphate (S1P) is a membrane-derived lysophospholipid. The S1P gradient between tissues and the circulatory system has a key role in regulating the trafficking of immune cells as autoreactive B and T lymphocytes. S1P receptor modulators could be a safe and efficacious alternative mechanism for reducing inflammation in immune-mediated disorders, including UC, by reducing lymphocyte egress from the lymph nodes to the bloodstream. Several S1P receptor modulators have been developed and tested in UC. Ozanimod is already approved by Food and Drug Administration (FDA) and European Medical Agency (EMA), while etrasimod and VTX002 are still under approval. Oral administration route, rapidity and reliable safety profile are the main advantages of this class of drugs. The aim of this review is to summarize the available evidence for the efficacy, safety, and pharmacokinetics of ozanimod, etrasimod, and VTX002 in UC.

Early Intestinal Ultrasound Predicts Long-Term Endoscopic Response to Biologics in Ulcerative Colitis.

BACKGROUND AND AIMS: The Milan ultrasound criteria [MUC] is a validated score to assess endoscopic activity in ulcerative colitis [UC]. MUC > 6.2 detects Mayo endoscopic score [MES] > 1. In this study we evaluated the predictive value of MUC for biologic treatment response, using colonoscopy [CS] as a reference standard. METHODS: Consecutive UC patients starting biologic therapy were included, and underwent CS, IUS, clinical assessment and faecal calprotectin [FC] measurement at baseline and within 1 year. In addition, IUS, clinical and FC assessments were performed at week 12. The primary objective was to evaluate whether ultrasound improvement [MUC ≤ 6.2] at week 12 predicted endoscopic improvement at reassessment [MES ≤ 1]. Endoscopic remission was defined as MES = 0. RESULTS: Forty-nine patients were included [59% under infliximab, 29% under vedolizumab, 8% under adalimumab, 4% under ustekinumab]. MUC ≤ 6.2 at week 12 was the only independent predictor for MES ≤ 1 and MES = 0 at reassessment (odds ratio [OR] 5.80, p = 0.010; OR 10.41, p = 0.041; respectively). MUC ≤ 6.2 at week 12 showed a negative predictive value of 96% for detecting MES = 0. A ≥2 reduction of the MUC predicted MES = 0 (area under the curve [AUC] 0.816). MUC ≤ 4.3 was the most accurate cut-off value for MES = 0 [AUC 0.876]. Guyatt's responsiveness ratio for the MUC was 1.73 [>0.8]. CONCLUSION: MUC ≤ 6.2 at week 12 predicts long-term endoscopic response. MUC is accurate in monitoring treatment response and may be used in both clinical trials and routine practice.