Ulcerative colitis.

Ulcerative colitis is a lifelong inflammatory disease affecting the rectum and colon to a variable extent. In 2023, the prevalence of ulcerative colitis was estimated to be 5 million cases around the world, and the incidence is increasing worldwide. Ulcerative colitis is thought to occur in people with a genetic predisposition following environmental exposures; gut epithelial barrier defects, the microbiota, and a dysregulated immune response are strongly implicated. Patients usually present with bloody diarrhoea, and the diagnosis is based on a combination of clinical, biological, endoscopic, and histological findings. The aim of medical management is, first, to induce a rapid clinical response and normalise biomarkers and, second, to maintain clinical remission and reach endoscopic normalisation to prevent long-term disability. Treatments for inducing remission include 5-aminosalicylic acid drugs and corticosteroids. Maintenance treatments include 5-aminosalicylic acid drugs, thiopurines, biologics (eg, anti-cytokines and anti-integrins), and small molecules (Janus kinase inhibitors and sphingosine-1-phosphate receptor modulators). Although the therapeutic options are expanding, 10-20% of patients still require proctocolectomy for medically refractory disease. The keys to breaking through this therapeutic ceiling might be the combination of therapeutics with precision and personalised medicine.

Long-term Outcome of Risankizumab in Crohn's Disease: a Real-world GETAID Study.

BACKGROUND & AIMS: The aim of this study was to assess the long-term effectiveness and safety of risankizumab maintenance treatment in a large real-world cohort of patients with Crohn's Disease (CD). METHODS: From May 2021 to August 2023, all consecutive patients with CD treated with risankizumab in 25 GETAID centers have been retrospectively included. The primary endpoint was steroid-free clinical remission (Harvey Bradshaw Index [HBI] <5) at 52 weeks. RESULTS: Of the 174 patients included, 99%, 93%, and 96% had been previously exposed to anti-TNF, vedolizumab, and ustekinumab, respectively. All patients had received ≥3 biologics, and 108 (62%) had previous intestinal resection. Median follow-up was 13.7 months (interquartile range, 10.0-18.1 months). The rates of steroid-free clinical remission and clinical remission at week 26 were 47% (72/152) and 52% (79/152), and 46% (58/125), and 48% (60/125) at week 52, respectively. Risankizumab persistence rates were 94%, 89%, and 79% at weeks 12, 26, and 52, respectively. At the end of follow-up, 45 (45/174; 26%) patients had discontinued risankizumab (loss of response, 42%; primary failure, 37%; intolerance, 13%). Thirty-six patients (36/174; 20.9%) were hospitalized, and 22 (22/174; 12.6%) required intestinal resection. Fifty-one patients (29%) had an adverse event, including 26 (15%) serious adverse events (CD flare, n = 17). One death (myocardial infarction) and one cancer (papillary thyroid carcinoma) were observed. CONCLUSION: This is the first real-life study to report long-term outcomes in patients with refractory CD treated with risankizumab. One-half of the patients achieved steroid-free clinical remission after 1 year, and the safety profile was consistent with the literature.

Evolving Short- and Long-Term Goals of Management of Inflammatory Bowel Diseases: Getting It Right, Making It Last.

Short- and long-term treatment targets in inflammatory bowel diseases (IBDs) evolved during the last decade, shifting from symptom control to endoscopic healing and patient-centered parameters. The STRIDE-II consensus placed these targets on a timeline from initiating treatment and introduced additional targets, normalization of serum and fecal biomarkers, restoration of quality of life, prevention of disability, and, in children, restoration of growth. Transmural healing in Crohn's disease and histologic healing in ulcerative colitis currently serve as adjunct measures to gauge remission depth. However, whether early treatment according to a treat-to-target paradigm affects the natural course of IBD remains unclear, leading to the need for prospective disease-modification trials. The SPIRIT consensus defined the targets for these trials to assess the long-term impact of early treatment on quality of life, disability, disease complications, risk of neoplastic lesions, and mortality. As further data emerge about the risk-benefit balance of aiming toward deeper healing, the targets in treating IBDs may continue to shift.

Selecting End Points for Disease-Modification Trials in Inflammatory Bowel Disease: the SPIRIT Consensus From the IOIBD.

BACKGROUND AND AIMS: Inflammatory bowel diseases (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), are chronic and disabling disorders. Prospective disease-modification trials to prevent disease progression are eagerly awaited. However, disease progression is not clearly defined. The objective of the Selecting End PoInts foR Disease-ModIfication Trials (SPIRIT) initiative was to achieve international expert consensus on the endpoints to be used in future IBD-disease modification trials. METHODS: This initiative under the auspices of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) began with a systematic literature search to evaluate the current evidence on the definition of disease progression in IBD. On October 22, 2019, a consensus meeting took place during the United European Gastroenterology Week (UEGW) Congress in Barcelona, during which predefined proposed statements were discussed in a plenary session and voted on anonymously. Agreement was defined as at least 75% of participants voting for any one statement. RESULTS: The group agreed that the ultimate therapeutic goal in both CD and UC is to prevent disease impact on patient's life (health-related quality of life, disability, fecal incontinence), midterm complications (encompass bowel damage in CD, IBD-related surgery and hospitalizations, disease extension in UC, extraintestinal manifestations, permanent stoma, short bowel syndrome), and long-term complications (gastrointestinal and extraintestinal dysplasia or cancer, mortality). CONCLUSIONS: Recommendations on which goals to achieve in disease-modification trials for preventing disease progression in patients with IBD are proposed by the SPIRIT consensus. However, these recommendations will require validation in actual clinical studies before implementation in disease-modification trials.

A Magnetic Resonance Imaging Index to Predict Crohn's Disease Postoperative Recurrence: The MONITOR Index.

BACKGROUND & AIMS: We developed and validated a magnetic resonance imaging-based index to predict Crohn's disease (CD) postoperative recurrence (POR). METHODS: Patients with CD who underwent a postoperative evaluation for recurrence (with colonoscopy and MRI no longer than 105 days apart) were included between 2006 and 2016 in University Hospital of Nancy, France. MRI items with good levels of intra-rater and inter-rater agreement (Gwet's coefficient ≥0.5) were selected. The MRI in Crohn's Disease to Predict Postoperative Recurrence (MONITOR) index's performance was assessed in terms of the area under the receiver operating characteristic curve (AUROC) and accuracy, by considering the Rutgeerts score as the gold standard. The MONITOR index was validated with a bootstrap method and an independent cohort. RESULTS: Seventy-three MRI datasets were interpreted by 2 radiologists. Seven items (bowel wall thickness, contrast enhancement, T2 signal increase, diffusion-weighted signal increase, edema, ulcers, and the length of the diseased segment) had a Gwet's coefficient ≥0.5 and were significantly associated with the Rutgeerts score, leading to their inclusion in the MONITOR index. All the items had a weighting of 1, except the "ulcers" item weighting 2.5, reflecting the higher adjusted odds ratio. The AUROC [95% confidence interval] for the prediction of endoscopic POR (Rutgeerts score >i1) was 0.80 [0.70-0.90]. The optimal threshold was a MONITOR index ≥1, giving a sensitivity of 79%, a specificity of 55%, a predictive positive value of 68%, and a predictive negative value of 68%. The bootstrap validation gave an AUROC of 0.85 [0.73-0.97]. In the validation cohort, a MONITOR index ≥1 gave a sensitivity of 87%, a specificity of 75%, a predictive positive value of 84.6%, and a predictive negative value of 75%. CONCLUSIONS: The MONITOR index is an efficient, reliable, easy-to-apply tool that can be used in clinical practice to predict the POR of CD.

Prevalence of Self-Reported Venous Thromboembolism and Cardiovascular Risk Factors in Patients with Ulcerative Colitis: The GETAID FOCUS Study.

BACKGROUND AND AIMS: Patients with inflammatory bowel disease have an increased risk of venous thromboembolism (VTE) and cardiovascular disease (CVD). The study aims to determine the prevalence of CVD and VTE risk factors in a large population of patients with ulcerative colitis (UC). METHODS: We conducted a cross-sectional study in 33 French and Belgium referral centers. A questionnaire was developed to explore self-reported risk factors for VTE and CVD, based on the latest international guidelines, in consecutive patients with UC. RESULTS: A total of 1071 patients with UC were included. There were 539 women (50.3%), and the median age of patients was 44 years [32; 57]. The median disease duration was 10 years [6; 17]. In the cohort, 36.5% of patients reported no cardiovascular risk factor (CVRF) and 72% had ≤ 1 CVRF. Regarding cardiovascular risk markers (CVRM) 36.9% of patients reported no CVRM and 78% had ≤ 1 CVRM. Of the 1071 patients, 91.3% of patients reported no VTE strong risk factor and 96% had ≤ 1 VTE moderate risk factor. CONCLUSION: This is the first cohort specifically designed to assess both VTE and CVD risks in patients with UC. More than one third of patients with UC had no CVRF and around three quarters had ≤ 1 CVRF. In addition, more than nine out of ten patients had no VTE strong risk factor and ≤ 1 moderate risk factor. Physicians should be aware of these factors in their patients.

Application of Artificial Intelligence to Gastroenterology and Hepatology.

Since 2010, substantial progress has been made in artificial intelligence (AI) and its application to medicine. AI is explored in gastroenterology for endoscopic analysis of lesions, in detection of cancer, and to facilitate the analysis of inflammatory lesions or gastrointestinal bleeding during wireless capsule endoscopy. AI is also tested to assess liver fibrosis and to differentiate patients with pancreatic cancer from those with pancreatitis. AI might also be used to establish prognoses of patients or predict their response to treatments, based on multiple factors. We review the ways in which AI may help physicians make a diagnosis or establish a prognosis and discuss its limitations, knowing that further randomized controlled studies will be required before the approval of AI techniques by the health authorities.

Ulcerative Colitis and Crohn's Disease Have Similar Burden and Goals for Treatment.

It is unclear whether ulcerative colitis (UC) is a progressive disease similar to Crohn's disease (CD). Patients with UC often are undertreated because of the possibility of curative colectomy and the perception that the disease burden is lower than that of CD. We discuss findings from studies that aimed to determine whether UC and CD have the same disease burden and should be treated in the same intensive way. We discuss the similarities between CD and UC, including effects on quality of life, long-term complications, strictures, increased risk of cancer, pseudopolyps, functional abnormalities, and anorectal dysfunction. Contrary to the generally accepted idea, surgery cannot cure UC. Postoperative complications, especially pouchitis and fecal incontinence, affect more than one third of patients. CD and UC each pose substantial economic burdens. Monitoring, treatments, and goals of therapy are similar for all inflammatory bowel diseases. Earlier initiation of disease-modifying drugs might reduce the progression of UC and reduce its burden after surgery, although UC might not cause the irreversible damage observed in patients with CD.

JAK selectivity for inflammatory bowel disease treatment: does it clinically matter?

The two major forms of inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), are chronic immune-mediated conditions characterised by an increased production of pro-inflammatory cytokines that act as critical drivers of intestinal inflammation. Anti-cytokine therapy has been shown to improve clinical outcomes in IBD. Janus kinases (JAKs) are tyrosine kinases that bind different intracellular cytokine receptors, leading to phosphorylation of signal transducer and activation of transcription molecules implicated on targeted gene transcription. Four isoforms of JAKs have been described: JAK1, JAK2, JAK3 and TYK2. Oral JAK inhibitors (JAKi) have been developed as synergic anti-cytokine therapy in IBD, showing different selectivity towards JAK isoforms. Tofacitinib, a pan-JAK inhibitor, has been recently approved for the treatment of moderate-to-severe UC. With the aim of improving the benefit: risk ratio of this drug class, several second-generation subtype-selective JAKi are under development. However, whether selective inhibition of JAK isoforms is associated with an increased clinical efficacy and/or a better safety profile remains debatable. The aim of this review is to critically review the preclinical and clinical data for the differential selectivity of JAK inhibitors and to summarise the potential clinical implications of the selective JAK inhibitors under development for UC and CD.

Artificial intelligence for characterization of colorectal polyps: Prospective multicenter study.

Background and study aims Optical diagnosis poses challenges to implementation of "resect and discard" strategies. This study aimed to assess the feasibility and performance of a new commercially available system for colorectal polyps. Patients and methods Nine expert endoscopists in three centers performed colonoscopies using artificial intelligence-equipped colonoscopes (CAD EYE, Fujifilm). Histology and predictions were compared, with hyperplastic polyps and sessile serrated lesions grouped for analysis. Results Overall, 253 polyps in 119 patients were documented (n=152 adenomas, n=78 hyperplastic polyps, n=23 sessile serrated lesions). CAD EYE detected polyps before endoscopists in 81 of 253 cases (32%). The mean polyp size was 5.5 mm (SD 0.6 mm). Polyp morphology was Paris Ip (4 %), Is (28 %), IIa (60 %), and IIb (8 %). CAD EYE achieved a sensitivity of 80%, specificity of 83%, positive predictive value (PPV) of 96%, and negative predictive value (NPV) of 72%. Expert endoscopists had a sensitivity of 88%, specificity of 83%, PPV of 96%, and NPV of 72%. Diagnostic accuracy was similar between CAD EYE (81%) and endoscopists (86%). However, sensitivity was greater with endoscopists as compared with CAD EYE ( P <0.05). CAD EYE classified sessile serrated lesions as hyperplasia in 22 of 23 cases, and endoscopists correctly classified 16 of 23 cases. Conclusions The CAD EYE system shows promise for detecting and characterizing colorectal polyps. Larger studies are needed, however, to confirm these findings.

Role of ICAM-1 in the Adhesion of T Cells to Enteric Glia: Perspectives in the Formation of Plexitis in Crohn's Disease.

BACKGROUND & AIMS: The presence of myenteric plexitis in the proximal resection margins is a predictive factor of early postoperative recurrence in Crohn's disease. To decipher the mechanisms leading to their formation, T-cell interactions with enteric neural cells were studied in vitro and in vivo. METHODS: T cells close to myenteric neural cells were retrospectively quantified in ileocolonic resections from 9 control subjects with cancer and 20 patients with Crohn's disease. The mechanisms involved in T-cell adhesion were then investigated in co-cultures of T lymphocytes with enteric glial cells (glia). Finally, the implication of adhesion molecules in the development of plexitis and colitis was studied in vitro but also in vivo in Winnie mice. RESULTS: The mean number of T cells close to glia, but not neurons, was significantly higher in the myenteric ganglia of relapsing patients with Crohn's disease (2.42 ± 0.5) as compared with controls (0.36 ± 0.08, P = .0007). Co-culture experiments showed that exposure to proinflammatory cytokines enhanced T-cell adhesion to glia and increased intercellular adhesion molecule-1 (ICAM-1) expression in glia. We next demonstrated that T-cell adhesion to glia was inhibited by an anti-ICAM-1 antibody. Finally, using the Winnie mouse model of colitis, we showed that the blockage of ICAM-1/lymphocyte function-associated antigen-1 (LFA-1) with lifitegrast reduced colitis severity and decreased T-cell infiltration in the myenteric plexus. CONCLUSIONS: Our present work argues for a role of glia-T-cell interaction in the development of myenteric plexitis through the adhesion molecules ICAM-1/LFA-1 and suggests that deciphering the functional consequences of glia-T-cell interaction is important to understand the mechanisms implicated in the development and recurrence of Crohn's disease.

Tofacitinib for Patients with Anti-TNF Refractory Ulcerative Proctitis: A Multicentre Cohort Study from the GETAID.

BACKGROUND: Although ulcerative proctitis [UP] can dramatically impair quality of life, treatment efficacy has been poorly investigated in UP as it was historically excluded from phase 2/3 randomised controlled trials in ulcerative colitis. Our aim was to assess the effectiveness and safety of tofacitinib for the treatment of UP. METHODS: We conducted a retrospective, multicentre study in 17 GETAID centres, including consecutive patients with UP treated with tofacitinib. The primary endpoint was steroid-free remission between Week 8 and Week 14, defined as a partial Mayo score of 2 [and no individual subscore above 1]. Secondary outcomes included clinical response and steroid-free remission after induction and at 1 year. RESULTS: All the 35 enrolled patients previously received anti-tumour necrosis factor [TNF] therapy and 88.6% were exposed to at least two lines of biologics. At baseline, the median partial Mayo score was 7 (intequartile range [IQR] [5.5-7]). After induction [W8-W14], 42.9% and 60.0% of patients achieved steroid-free remission and clinical response, respectively. At 1 year, the steroid-free clinical remission and clinical response rates were 39.4% and 45.5%, respectively, and 51.2% [17/33] were still receiving tofacitinib treatment. Survival without tofacitinib withdrawal was estimated at 50.4% (95% confidence interval [CI] [35.5-71.6]) at 1 year. Only a lower partial Mayo at baseline was independently associated with remission at induction (0dds ratio [OR] = 0.56 for an increase of 1, (95% CI [0.33-0.95], p = 0.03). Five [14.3%] adverse events were reported, with one leading to treatment withdrawal [septic shock secondary to cholecystitis]. CONCLUSION: Tofacitinib may offer a therapeutic option for patients with refractory UP.

Can we change the natural course of inflammatory bowel disease?

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are lifelong diseases characterized by chronic inflammation of the gastrointestinal tract leading to its progressive and irreversible destruction. Whether early initiation of IBD-specific therapy impacts the long-term course of the disease remains unclear and has to be further explored in prospective disease-modification trials. Historically, surgery and hospitalization rates have been the surrogate markers to measure disease progression in IBD, providing an overview of the effectiveness of medical therapies. However, neither surgery nor hospitalization necessarily reflects a fail in therapeutic medical management, and many confounding factors make them biased outcomes. The Selecting Endpoints for Disease-Modification Trials consensus has defined the disease-modification endpoints required for these trials, including the impact of the disease on patient's life (health-related quality of life, disability, and fecal incontinence), the mid-term disease complications (bowel damage in CD, IBD-related surgery and hospitalizations, disease extension in UC, extra-intestinal manifestations, permanent stoma, short bowel syndrome), and the development of dysplasia/cancer and mortality in the long term. Most available data in the literature regarding the impact of current therapies on disease progression focused on anti-tumor necrosis factor agents and are based on retrospective or post-hoc studies. Thus, prospective disease-modification trials are pressingly required to explore the effectiveness of early intensified treatment in patients with severe disease or at risk for disease progression.

Enteric glia at center stage of inflammatory bowel disease.

Although our understanding of the pathophysiology of inflammatory bowel disease (IBD) is increasing, the expanding body of knowledge does not simplify the equation but rather reveals diverse, interconnected, and complex mechanisms in IBD. In addition to immune overactivation, defects in intestinal epithelial barrier (IEB) functioning, dysbiosis, and structural and functional abnormalities of the enteric nervous system are emerging as new elements contributing to the development of IBD. In addition to molecular changes in IBD, enteric glia from patients with Crohn's disease (CD) exhibits the inability to strengthen the IEB; these defects are not observed in patients with ulcerative colitis. In addition, there is a growing body of work describing that enteric glia interacts with not only enterocytes and enteric neurons but also other local cellular neighbours. Thus, because of their functions as connectors and regulators of immune cells, IEB, and microbiota, enteric glia could be the keystone of digestive homeostasis that is lacking in patients with CD.

Effectiveness and safety of risankizumab induction therapy for 100 patients with Crohn's disease: A GETAID multicentre cohort study.

BACKGROUND: Phase III trials have demonstrated the efficacy of risankizumab in moderate-to-severe Crohn's disease (CD), but no real-world data are currently available. We aimed to assess the short-term effectiveness and safety of risankizumab in patients with CD. METHODS: From May 2021 to May 2022, all patients with refractory luminal CD treated with risankizumab in 22 French GETAID centres were retrospectively included. The primary endpoint was steroid-free clinical remission at week 12 (Harvey-Bradshaw [HB] score <5). Secondary endpoints included clinical response (≥3-point decrease of HB score and/or (HB) score <5), biochemical remission (CRP ≤ 5 mg/L), need for CD-related surgery and adverse events. RESULTS: Among the 100 patients included, all have been previously exposed to anti-TNF agents, 94 to vedolizumab, 98 to ustekinumab (all exposed to at least three biologics) and 61 had a previous intestinal resection. All but three (97%) received a 600 mg risankizumab intravenous induction at weeks 0-4-8. At week 12, steroid-free clinical remission was observed in 45.8% of patients, clinical remission in 58% and clinical response in 78.5%. In subgroup analysis restricted to patients with objective signs of inflammation at baseline (n = 79), steroid-free clinical remission at week 12 was observed in 39.2% of patients. Biochemical remission was observed in 50% of patients. Six patients discontinued risankizumab before the week 12 visit due to lack of efficacy. CD-related hospitalisation was needed in six patients, and three underwent intestinal resection. In multivariable analysis, only a history of ustekinumab loss of response (vs primary failure) (odds ratio (OR), 2.80; 95% CI: 1.07-7.82; p = 0.041) was significantly associated with clinical remission at week 12. Twenty adverse events (AE) occurred in 20 patients including 7 serious AE corresponding to 6 CD exacerbation and one severe hypertension. CONCLUSION: In a cohort of highly refractory patients with luminal CD and multiple prior drug failures including ustekinumab, risankizumab induction provided a clinical response in about 3 out of 4 patients and steroid-free clinical remission in about half of patients.

The risk of COVID-19 in IBD patients is increased by urban living and is not influenced by disease activity or intravenous biologics.

Background: Patients with inflammatory bowel disease (IBD) may have a modified immune response to SARS-CoV-2. The objectives were to evaluate the prevalence of COVID-19 in patients treated with infliximab or vedolizumab, to analyze the factors associated with the infection, the impact of treatments and trough levels. Methods: Patients with IBD treated with intravenous biologics in 14 French centers were included between March and June 2020 and followed-up for 6 months. Blood samples were collected for serologies and trough levels. The analysis of factors associated with COVID-19 was conducted in a matched 1:1 case-control sub-study with positive patients. Results: In total, 1026 patients were included (74.9% infliximab). Over the follow-up period, 420 patients reported the occurrence of COVID-19 symptoms; 342 had been tested of whom 18 were positive. At the end of follow-up, 38 patients had a positive serology. Considering both nasal tests and serologies together, 46 patients (4.5%) had been infected. The risk of COVID-19 was related neither to the use of treatments (whatever the trough levels) nor to disease activity. Infections were more frequent when using public transport or living in flats in urban areas. Conclusions: The prevalence rate of COVID-19 in this IBD population treated with intravenous infliximab or vedolizumab was the same as the one in the French population before the start of the vaccination campaign. The risk was increased by urban living and was not influenced by disease activity or biologics. Sanitary barrier measures remain the best way to protect against SARS-CoV-2 in patients with IBD in biological therapy.