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Background: Patient-reported outcome measures [PROMs] are key to documenting outcomes that matter most to patients and are increasingly important to commissioners of health care seeking value. We report the first series of the ICHOM Standard Set for Inflammatory Bowel Disease [IBD]., Methods: Patients treated for ulcerative colitis [UC] or Crohn's disease [CD] in our centre were offered enrolment into the web-based TrueColours-IBD programme. Through this programme, e-mail prompts linking to validated questionnaires were sent for symptoms, quality of life, and ICHOM IBD outcomes., Results: The first 1299 consecutive patients enrolled [779 UC, 520 CD] were studied with median 270 days of follow-up (interquartile range [IQR] 116, 504). 671 [52%] were female, mean age 42 years (standard deviation [sd] 16), mean body mass index [BMI] 26 [sd 5.3]. At registration, 483 [37%] were using advanced therapies. Median adherence to fortnightly quality of life reporting and quarterly outcomes was 100% [IQR 48, 100%] and 100% [IQR 75, 100%], respectively. In the previous 12 months, prednisolone use was reported by 229 [29%] patients with UC vs 81 [16%] with CD, p <0.001; 202 [16%] for <3 months; and 108 [8%] for >3 months. An IBD-related intervention was reported by 174 [13%] patients, and 80 [6%] reported an unplanned hospital admission. There were high rates of fatigue [50%] and mood disturbance [23%]., Conclusions: Outcomes reported by patients illustrate the scale of the therapeutic deficit in current care. Proof of principle is demonstrated that PROM data can be collected continuously with little burden on health care professionals. This may become a metric for quality improvement programmes or to compare outcomes., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

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., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aim: Inflammatory bowel disease (IBD) is emerging in the newly industrialized countries of South Asia, South-East Asia, and the Middle East, yet epidemiological data are scarce., Methods: We performed a cross-sectional study of IBD demographics, disease phenotype, and treatment across 38 centers in 15 countries of South Asia, South-East Asia, and Middle East. Intergroup comparisons included gross national income (GNI) per capita., Results: Among 10 400 patients, ulcerative colitis (UC) was twice as common as Crohn's disease (CD), with a male predominance (UC 6678, CD 3495, IBD unclassified 227, and 58% male). Peak age of onset was in the third decade, with a low proportion of elderly-onset IBD (5% age > 60). Familial IBD was rare (5%). The extent of UC was predominantly distal (proctitis/left sided 67%), with most being treated with mesalamine (94%), steroids (54%), or immunomodulators (31%). Ileocolic CD (43%) was the commonest, with low rates of perianal disease (8%) and only 6% smokers. Diagnostic delay for CD was common (median 12 months; interquartile range 5-30). Treatment of CD included mesalamine, steroids, and immunomodulators (61%, 51%, and 56%, respectively), but a fifth received empirical antitubercular therapy. Treatment with biologics was uncommon (4% UC and 13% CD), which increased in countries with higher GNI per capita. Surgery rates were 0.1 (UC) and 2 (CD) per 100 patients per year., Conclusions: The IBD-ENC cohort provides insight into IBD in South-East Asia and the Middle East, but is not yet population based. UC is twice as common as CD, familial disease is uncommon, and rates of surgery are low. Biologic use correlates with per capita GNI., (© 2022 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background & Aims: Monogenic forms of inflammatory bowel disease (IBD) illustrate the essential roles of individual genes in pathways and networks safeguarding immune tolerance and gut homeostasis., Methods: To build a taxonomy model, we assessed 165 disorders. Genes were prioritized based on penetrance of IBD and disease phenotypes were integrated with multi-omics datasets. Monogenic IBD genes were classified by (1) overlapping syndromic features, (2) response to hematopoietic stem cell transplantation, (3) bulk RNA-sequencing of 32 tissues, (4) single-cell RNA-sequencing of >50 cell subsets from the intestine of healthy individuals and patients with IBD (pediatric and adult), and (5) proteomes of 43 immune subsets. The model was validated by addition of newly identified monogenic IBD defects. As a proof-of-concept, we explore the intersection between immunometabolism and antimicrobial activity for a group of disorders (G6PC3/SLC37A4)., Results: Our quantitative integrated taxonomy defines the cellular landscape of monogenic IBD gene expression across 102 genes with high and moderate penetrance (81 in the model set and 21 genes in the validation set). We illustrate distinct cellular networks, highlight expression profiles across understudied cell types (e.g., CD8 + T cells, neutrophils, epithelial subsets, and endothelial cells) and define genotype-phenotype associations (perianal disease and defective antimicrobial activity). We illustrate processes and pathways shared across cellular compartments and phenotypic groups and highlight cellular immunometabolism with mammalian target of rapamycin activation as one of the converging pathways. There is an overlap of genes and enriched cell-specific expression between monogenic and polygenic IBD., Conclusion: Our taxonomy integrates genetic, clinical and multi-omic data; providing a basis for genomic diagnostics and testable hypotheses for disease functions and treatment responses., (Copyright © 2022 AGA Institute. All rights reserved.)

Current inflammatory bowel disease (IBD) therapies are ineffective in a high proportion of patients. Combining bulk and single-cell transcriptomics, quantitative histopathology and in situ localization across three cohorts of patients with IBD (total n = 376), we identify coexpressed gene modules within the heterogeneous tissular inflammatory response in IBD that map to distinct histopathological and cellular features (pathotypes). One of these pathotypes is defined by high neutrophil infiltration, activation of fibroblasts and vascular remodeling at sites of deep ulceration. Activated fibroblasts in the ulcer bed display neutrophil-chemoattractant properties that are IL-1R, but not TNF, dependent. Pathotype-associated neutrophil and fibroblast signatures are increased in nonresponders to several therapies across four independent cohorts (total n = 343). The identification of distinct, localized, tissular pathotypes will aid precision targeting of current therapeutics and provides a biological rationale for IL-1 signaling blockade in ulcerating disease., (© 2021. The Author(s).)

Background: It is important to identify patients with monogenic IBD as management may differ from classical IBD. In this position statement we formulate recommendations for the use of genomics in evaluating potential monogenic causes of IBD across age groups., Methods: The consensus included paediatric IBD specialists from the Paediatric IBD Porto group of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and specialists from several monogenic IBD research consortia. We defined key topics and performed a systematic literature review to cover indications, technologies (targeted panel, exome and genome sequencing), gene panel setup, cost-effectiveness of genetic screening, and requirements for the clinical care setting. We developed recommendations that were voted upon by all authors and Porto group members (32 voting specialists)., Results: We recommend next-generation DNA-sequencing technologies to diagnose monogenic causes of IBD in routine clinical practice embedded in a setting of multidisciplinary patient care. Routine genetic screening is not recommended for all IBD patients. Genetic testing should be considered depending on age of IBD-onset (infantile IBD, very early-onset IBD, paediatric or young adult IBD), and further criteria, such as family history, relevant comorbidities, and extraintestinal manifestations. Genetic testing is also recommended in advance of hematopoietic stem cell transplantation. We developed a diagnostic algorithm that includes a gene panel of 75 monogenic IBD genes. Considerations are provided also for low resource countries., Conclusions: Genomic technologies should be considered an integral part of patient care to investigate patients at risk for monogenic forms of IBD., (Copyright © 2020 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Anti-tumour necrosis factor (anti-TNF) therapy increases the risk of tuberculosis (TB). Given limitations of screening techniques, it remains uncertain if patients receiving anti-TNF in TB endemic regions should be screened for latent infection with chemoprophylaxis restricted to those with proven infection, or if all patients should receive chemoprophylaxis., Aims: To compare the incidence of active TB with infliximab (IFX) following targeted and universal TB chemoprophylaxis, and to determine the rates of adverse events (AE) related to TB chemoprophylaxis METHODS: A multi-centre retrospective cohort study was performed at 18 hospitals in China of 1968 adult patients with IBD receiving IFX from 2009 to 2017. TB screening prior to IFX was performed with chest X-ray and/or computed tomography [CT] and immune reactivity testing (interferon-γ release assay and/or tuberculin skin test). Patients were followed-up for a minimum of 3 months after IFX discontinuation, or until last hospital visit if IFX therapy was ongoing. Targeted strategy was defined as TB chemoprophylaxis only for patients with a positive latent TB screen, with universal strategy defined as TB chemoprophylaxis for all patients., Results: Mean follow-up was 1.07 ± 0.87 years with a total follow-up of 2102 patient-years. There were 1433 patients in the targeted and 483 patients in the universal TB chemoprophylaxis groups, with no significant difference in the incidence rates of active TB between groups (673.3 per 100 000 population per year vs 891.5 per 100 000 population per year, P = 0.60). In the targeted group, 55/1433 patients received TB chemoprophylaxis compared with 483/483 in the universal group, with significantly fewer AEs related to TB chemoprophylaxis in the targeted compared to the universal group (0.35% (5/1433) vs 6.8% (33/483), P < 0.05)., Conclusions: In this study of patients receiving IFX in a TB endemic area, universal chemoprophylaxis was not associated with a reduced risk of active TB when compared to a targeted chemoprophylaxis strategy, and AEs were more common. This supports the use of targeted TB chemoprophylaxis when anti-TNF therapy is initiated in TB endemic regions., (© 2020 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P < 4 × 10 -10 ), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10 -10 ). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis.

Introduction: Patients with inflammatory bowel disease (IBD) undergoing polypectomy are recommended by current guidelines to have biopsies taken from adjacent mucosa to determine whether there is dysplasia present. With improvements in endoscopic imaging, it is now possible to characterize colonic lesions with higher levels of confidence than previously. We have reviewed the diagnostic yield of polyp-adjacent biopsies in IBD., Materials and Methods: A systematic search of our histopathology database revealed cases in which polyps had been endoscopically resected or biopsied in patients with IBD. Endoscopy reports and medical records were reviewed, and patient demographic and disease-specific details were recorded, along with details of polyp characteristics and histopathology outcomes., Results: Three hundred and two polyps were biopsied or resected in 131 patients undergoing 178 colonoscopies. The median polyp size was 4 mm (range 1-45), and the predominant morphology was Paris 0-Is (n = 98, 32%). The histology was tubular adenoma in 76 (25%), tubulovillous adenoma in 14 (5%), hyperplastic in 112 (37%), post-inflammatory in 32 (11%), sessile serrated polyp in 31 (10%), traditional serrated adenoma in 2 (0.7%), flat high-grade dysplasia or cancer in 2 (0.7%) and other in 33 (11%). Dysplasia in adjacent biopsies was detected in 2 patients (0.7%), and was endoscopically visible in both cases. The proportion of endoscopically unsuspected dysplasia was 0/300 (0%, 95% CI 0-1.6%)., Conclusion: The diagnostic yield for polyp-adjacent biopsies in patients with IBD is negligible. With high-definition technology and chromoendoscopy, it may no longer be necessary to biopsy endoscopically normal adjacent tissue to detect invisible dysplasia.

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex chronic inflammatory conditions of the gastrointestinal tract that are driven by perturbed cytokine pathways. Anti-tumor necrosis factor-α (TNF) antibodies are mainstay therapies for IBD. However, up to 40% of patients are nonresponsive to anti-TNF agents, which makes the identification of alternative therapeutic targets a priority. Here we show that, relative to healthy controls, inflamed intestinal tissues from patients with IBD express high amounts of the cytokine oncostatin M (OSM) and its receptor (OSMR), which correlate closely with histopathological disease severity. The OSMR is expressed in nonhematopoietic, nonepithelial intestinal stromal cells, which respond to OSM by producing various proinflammatory molecules, including interleukin (IL)-6, the leukocyte adhesion factor ICAM1, and chemokines that attract neutrophils, monocytes, and T cells. In an animal model of anti-TNF-resistant intestinal inflammation, genetic deletion or pharmacological blockade of OSM significantly attenuates colitis. Furthermore, according to an analysis of more than 200 patients with IBD, including two cohorts from phase 3 clinical trials of infliximab and golimumab, high pretreatment expression of OSM is strongly associated with failure of anti-TNF therapy. OSM is thus a potential biomarker and therapeutic target for IBD, and has particular relevance for anti-TNF-resistant patients.

Most patients with inflammatory bowel diseases (IBD) are offered conventional medical therapy, because emerging therapies for IBD are regulated by health-care jurisdiction and often limited to academic centres. This review distils current evidence to provide a pragmatic approach to conventional IBD therapy, including aminosalicylates, corticosteroids, thiopurines, methotrexate, calcineurin inhibitors, infliximab and adalimumab. It addresses drug efficacy, safety and salient practice points for optimal and appropriate practice.

Inflammatory bowel disease (IBD) is a disease-specific risk factor for incident and recurrent venous thromboembolism (VTE). The reasons are acquired, multifactorial, and related to prothrombotic aberrations during active disease, although the mechanisms remain incompletely elucidated. VTE represents a potentially life-threatening extraintestinal manifestation of IBD, but the associated morbidity and mortality can be reduced by appropriate use of thromboprophylaxis. Nevertheless, despite international guidelines advocating thromboprophylaxis in hospitalised patients with IBD, practice is highly variable, since 65% of gastroenterologists may not use pharmacological VTE prophylaxis in hospitalised patients with acute severe colitis. Furthermore, there is no guidance on appropriate prophylaxis for ambulatory outpatients with active disease who are at an appreciable risk of VTE. Thus the question: are we tailoring thromboprophylaxis to those patients with IBD who are most at risk?, (© 2013.)

Recent studies have identified mucosal healing on endoscopy as a key prognostic parameter in the management of inflammatory bowel diseases (IBD), thus highlighting the role of endoscopy for monitoring of disease activity in IBD. In fact, mucosal healing has emerged as a key treatment goal in IBD that predicts sustained clinical remission and resection-free survival of patients. The structural basis of mucosal healing is an intact barrier function of the gut epithelium that prevents translocation of commensal bacteria into the mucosa and submucosa with subsequent immune cell activation. Thus, mucosal healing should be considered as an initial event in the suppression of inflammation of deeper layers of the bowel wall, rather than as a sign of complete healing of gut inflammation. In this systematic review, the clinical studies on mucosal healing are summarised and the effects of anti-inflammatory or immunosuppressive drugs such as 5-aminosalicylates, corticosteroids, azathioprine, ciclosporin and anti-TNF antibodies (adalimumab, certolizumab pegol, infliximab) on mucosal healing are discussed. Finally, the implications of mucosal healing for subsequent clinical management in patients with IBD are highlighted.

Anemia is common in inflammatory bowel disease (IBD), with a prevalence ranging from 8.8% to 73.7%. This wide range reflects the definitions used and the populations studied. Although many patients are reported to be asymptomatic, systematic studies have shown anemia to have a significant impact on quality of life. Consequently treatment should be instituted early. The commonest cause of anemia in IBD is iron deficiency, predominantly related to gastrointestinal blood loss. Anemia of chronic disease often occurs concomitantly, due to cytokine-mediated impaired erythropoiesis and dysregulated iron metabolism. Oral iron is a simple and effective method for treating iron deficiency, but requires long courses of treatment. It is also theoretically implicated with worsening intestinal inflammation, via the production of toxic reactive oxygen species. Intravenous iron avoids these concerns, especially with the development of ferric carboxymaltose, which allow up to 1000mg to be given rapidly. In patients failing to respond to intravenous iron, the anemia of chronic disease is most likely to be causative. In this setting evidence suggests that additional erythropoietin therapy can be effective. Blood transfusions should be avoided as part of routine management and reserved for patients with substantial acute gastro-intestinal bleeding, where there is a risk of hemodynamic compromise. This article discusses the underlying physiology of anemia in IBD, and presents the current evidence supporting treatment options available.

This paper in the series from the World Congress of Gastroenterology addresses the safety and immunogenicity of biological therapy. The safety profile in randomized controlled studies of all biological agents in Crohn's disease (CD) and ulcerative colitis has been generally favorable, but a small percentage of patients experience severe side effects on biological therapy, including pneumonia, tuberculosis, lymphoma, demyelination, drug-induced lupus, or hepatotoxicity. Although there is unequivocal evidence of an increased risk of serious infection among patients with rheumatoid arthritis treated with anti-tumor necrosis factor therapy, the evidence is less clear in CD. The risk of infection may be increased by combination therapy with steroids and/or immunomodulators. There is a specific risk of the rare γ δ hepatosplenic lymphoma that appears to have a predeliction for young males on combination therapy. The α4 integrin antagonist natalizumab also carries a specific risk of progressive multifocal leucoencephalopathy and reactivation of JC virus infection. The immunogenicity of biological therapy is complex: all agents are potentially immunogenic and this can be reduced by combination with immunomodulators. This may enhance both therapeutic efficacy and the risk of infection or malignancy, so the balance of risk and benefit must be judged for individual patients.

Results of experimental and genetic studies have highlighted the role of the IL-23/IL-17 axis in the pathogenesis of inflammatory bowel disease (IBD). IL-23-driven inflammation has been primarily linked to Th17 cells; however, we have recently identified a novel population of innate lymphoid cells (ILCs) in mice that produces IL-17, IL-22, and IFN-γ in response to IL-23 and mediates innate colitis. The relevance of ILC populations in human health and disease is currently poorly understood. In this study, we have analyzed the role of IL-23-responsive ILCs in the human intestine in control and IBD patients. Our results show increased expression of the Th17-associated cytokine genes IL17A and IL17F among intestinal CD3⁻ cells in IBD. IL17A and IL17F expression is restricted to CD56⁻ ILCs, whereas IL-23 induces IL22 and IL26 in the CD56⁺ ILC compartment. Furthermore, we observed a significant and selective increase in CD127⁺CD56⁻ ILCs in the inflamed intestine in Crohn's disease (CD) patients but not in ulcerative colitis patients. These results indicate that IL-23-responsive ILCs are present in the human intestine and that intestinal inflammation in CD is associated with the selective accumulation of a phenotypically distinct ILC population characterized by inflammatory cytokine expression. ILCs may contribute to intestinal inflammation through cytokine production, lymphocyte recruitment, and organization of the inflammatory tissue and may represent a novel tissue-specific target for subtypes of IBD.

The thiopurines azathioprine and 6-mercaptopurine are effective both for active disease and for maintaining remission in both Crohn's disease and ulcerative colitis. This review describes criteria for starting thiopurines (two or more courses of steroids in a calendar year, relapse as prednisolone is reduced below 15 mg/day, within 6 weeks of stopping steroids) and the benefits of continuing treatment for up to 5 years. Challenging issues, such as thiopurine intolerance, relative merits of azathioprine, 6-mercaptopurine, monitoring therapy and thiopurines in pregnancy are addressed.

Precision medicine in immune-mediated inflammatory diseases (IMIDs) requires a cellular understanding of treatment response. We describe a therapeutic atlas for Crohns disease (CD) and ulcerative colitis (UC) following adalimumab, an anti-tumour necrosis factor (anti-TNF) treatment. We generated ~1 million single-cell transcriptomes, organised into 109 cell states, from 216 gut biopsies (41 subjects), revealing disease-specific differences. A systems biology-spatial analysis identified granuloma signatures in CD and interferon (IFN)-response signatures localising to T cell aggregates and epithelial damage in CD and UC. Pretreatment differences in epithelial and myeloid compartments were associated with remission outcomes in both diseases. Longitudinal comparisons demonstrated disease progression in nonremission: myeloid and T cell perturbations in CD and increased multi-cellular IFN signalling in UC. IFN signalling was also observed in rheumatoid arthritis (RA) synovium with a lymphoid pathotype. Our therapeutic atlas represents the largest cellular census of perturbation with the most common biologic treatment, anti-TNF, across multiple inflammatory diseases.

Mesalazine is an established and recommended first-line treatment for mild-tomoderate ulcerative colitis (UC). For patients with moderately active UC, the choice to use mesalazine or to initiate treatment with an oral corticosteroid or anti-tumor necrosis factor (TNF) agent is not clearly informed from current guidelines. The use of mesalazine is supported by robust clinical evidence supporting its efficacy at inducing remission in patients with moderately active disease. A key advantage of mesalazine is its tolerability profile being similar to that of placebo, which contrasts with that of the corticosteroids and advanced therapies, where there is the potential for significant toxicities. Mesalazine also has cost advantages over anti-TNFs and other advanced therapies. Evidence supports the consideration of all patients with moderately active UC for first-line mesalazine therapy at an optimized dose of ≥4g/d (± 1g/d rectal). Patients responding to treatment within 2 weeks should continue at ≥4g/d for at least 6 months before a dose reduction is considered, since this then alters the pattern of disease. [ABSTRACT FROM AUTHOR]

To understand current thinking and clinical decision-making in the treatment and management of patients with mild-to-moderate ulcerative colitis (UC). This multinational, survey-based study was conducted in 2021. Two meetings were held, involving 11 IBD specialists, that used a series of questions and discussion to identify all factors possibly related to the management of UC. The importance of identified factors was assessed using an online questionnaire covering three scenarios – active disease, remission and patient empowerment. Each factor was scored on a scale of 0 (very-unimportant) to 100 (very-important) within each scenario, by a separate group of healthcare professionals working in IBD. A total of 157 individual factors were identified by the 11 IBD specialists and scored in the three scenarios by 56 respondents (52; 93% specialist gastroenterologists) from Europe and North America (25; 45%), South America (19; 34%) and the Middle East, Asia and Australia (12; 21%). For all scenarios, factors related to educating patients regarding UC and its treatment and understanding of patient goals ranked highest, ahead of clinical considerations regarding disease activity and treatment history. Setting realistic short-term treatment targets was a key consideration. 5-ASA optimisation and use of faecal calprotectin monitoring were core strategies across the three scenarios tested. Support for patients during longer-term management of their disease, starting from initial flare, was an important recurring theme. The current management approach for mild-to-moderate UC was found to be guided primarily by the patient's perspectives and goals, alongside assessment of their medical and disease history. [ABSTRACT FROM AUTHOR]

Interferon regulating factor 5 (IRF5) is a multifunctional regulator of immune responses, and has a key pathogenic function in gut inflammation, but how IRF5 is modulated is still unclear. Having performed a kinase inhibitor library screening in macrophages, here we identify protein-tyrosine kinase 2-beta (PTK2B/PYK2) as a putative IRF5 kinase. PYK2-deficient macrophages display impaired endogenous IRF5 activation, leading to reduction of inflammatory gene expression. Meanwhile, a PYK2 inhibitor, defactinib, has a similar effect on IRF5 activation in vitro, and induces a transcriptomic signature in macrophages similar to that caused by IRF5 deficiency. Finally, defactinib reduces pro-inflammatory cytokines in human colon biopsies from patients with ulcerative colitis, as well as in a mouse colitis model. Our results thus implicate a function of PYK2 in regulating the inflammatory response in the gut via the IRF5 innate sensing pathway, thereby opening opportunities for related therapeutic interventions for inflammatory bowel diseases and other inflammatory conditions. The transcription factor, IRF5, has been implicated in the regulation of inflammation, but how IRF5 protein is activated is still unclear. Here the authors use inhibitor library screening, biochemical analyses and in vivo/ex vivo data to show that a protein tyrosine kinase, Pyk2, may be key for the activation of IRF5 in macrophages and inflammatory responses in the gut. [ABSTRACT FROM AUTHOR]

Pentasa (prolonged-release mesalazine [5-ASA]) has been available for >30 years as an effective treatment for mild-to-moderate ulcerative colitis (UC). A systematic literature review and meta-analysis was undertaken to provide an up-to-date evaluation of oral Pentasa efficacy and safety for induction and maintenance of remission. Literature searches were conducted in PubMed, Embase and Cochrane databases, from inception to 02 December 2020. Unpublished studies were also sourced. Meta-analyses using a random-effects model and Bayesian inference compared Pentasa (tablets, granules, capsules) against placebo and other 5-ASAs. Twelve studies involving 3674 patients treated with Pentasa were identified. Pentasa 2–4 g/day was superior to placebo at inducing (absolute risk difference [ARD] at 8 weeks 0.14, 95% CI 0.07‒0.21; p <.001) and maintaining (ARD 6-12 months 0.18, 95% CI 0.04‒0.33; p <.05) remission (clinical/endoscopic). Against other 5-ASAs, Pentasa had similar efficacy for induction (ARD <0.001, 95% CI −0.05‒0.05) and maintenance (ARD 0.01, 95% CI −0.07‒0.08) treatment using randomized controlled trial data. Upon inclusion of real-world study data, Pentasa was significantly better at maintaining remission compared both to Eudragit-S mesalazine and sulfasalazine (ARD 0.04, 95% CI 0.02‒0.06; p <.001). Pentasa (1–4 g/day) had similar treatment-related adverse event rates to placebo (ARD 0.02, 95% CI −0.03‒0.06) and Eudragit-L/S mesalazines (2.25-3 vs 2.4-3 g/day, respectively; ARD −0.03, 95% CI −0.12‒0.05), but was better tolerated than sulfasalazine (3 g/day) (ARD 0.07, 95% CI 0.003‒0.14; p <.05). This study confirms oral Pentasa is efficacious and well-tolerated in treating active UC and maintaining remission. The availability of multiple forms of Pentasa supports physicians' ability to individualize treatment and optimize dosing to improve outcomes. [ABSTRACT FROM AUTHOR]

Background: Primary sclerosing cholangitis (PSC) is closely associated with inflammatory bowel disease, particularly ulcerative colitis (UC), with an increased risk of biliary and colorectal malignancy. We sought to clarify the prevalence, characteristics and long‐term outcome of sub‐clinical PSC diagnosed by magnetic resonance cholangiogram (MRC) in patients with UC and normal liver biochemistry, with or without colorectal dysplasia (CRD). Methods: In this prospective case‐control study, 70 patients with UC and normal liver function (51 extensive UC, 19 CRD), 28 healthy volunteers (negative controls) and 28 patients with PSC and cholestasis (positive controls) underwent MRC and blood evaluation. MRC scans were interpreted blindly by two radiologists who graded individually, the scans as definitive for PSC, possible for PSC or normal. Clinical outcome was assessed by blood monitoring, abdominal imaging and endoscopic surveillance. Results: 7/51 (14%) with extensive UC and 4/19 (21%) with CRD had biliary abnormalities on MRC consistent with PSC. 7/11 (64%) with sub‐clinical PSC had isolated intrahepatic duct involvement. Sub‐clinical PSC was associated with advanced age (P =.04), non‐smoking (P =.03), pANCA (P =.04), quiescent colitis (P =.02), absence of azathioprine (P =.04) and high‐grade CRD (P =.03). Inter‐observer (kappa = 0.88) and intra‐observer (kappa = 0.96) agreement for MRC interpretation was high. No negative controls were assessed as definite PSC, 4/28 were considered on blinding as possible PSC. During follow‐up of sub‐clinical PSC (median 10.1(3.1‐11.9) years), four patients developed abnormal liver biochemistry, two had radiological progression of PSC and seven developed malignancy, including two biliary and one colorectal carcinoma. Conclusions: Prevalence of sub‐clinical PSC appears high in patients with extensive UC and normal liver biochemistry, with or without CRD. Disease progression and malignancy were identified on long‐term follow‐up. MRC should be considered for all patients with extensive UC or CRD to stratify surveillance. [ABSTRACT FROM AUTHOR]

We investigated the effects of inducing deep remission in patients with early Crohn's disease (CD). We collected follow-up data from 122 patients (mean age, 31.2 ± 11.3 y) with early, moderate to severe CD (median duration, 0.2 years; interquartile range, 0.1–0.5) who participated in the Effect of Tight Control Management on CD (CALM) study, at 31 sites, representing 50% of the original CALM patient population. Fifty percent of patients (n = 61) were randomly assigned to a tight control strategy (increased therapy based on fecal level of calprotectin, serum level of C-reactive protein, and symptoms), and 50% were assigned to conventional management. We categorized patients as those who were vs were not in deep remission (CD endoscopic index of severity scores below 4, with no deep ulcerations or steroid treatment, for 8 or more weeks) at the end of the follow-up period (median, 3.02 years; range, 0.05–6.26 years). The primary outcome was a composite of major adverse outcomes that indicate CD progression during the follow-up period: new internal fistulas or abscesses, strictures, perianal fistulas or abscesses, or hospitalization or surgery for CD. Kaplan-Meier and penalized Cox regression with bootstrapping were used to compare composite rates between patients who achieved or did not achieve remission at the end of the follow-up period. Major adverse outcomes were reported for 34 patients (27.9%) during the follow-up period. Significantly fewer patients in deep remission at the end of the CALM study had major adverse outcomes during the follow-up period (P =.01). When we adjusted for potential confounders, deep remission (adjusted hazard ratio, 0.19; 95% confidence interval, 0.07–0.31) was significantly associated with a lower risk of major adverse outcome. In an analysis of follow-up data from the CALM study, we associated induction of deep remission in early, moderate to severe CD with decreased risk of disease progression over a median time of 3 years, regardless of tight control or conventional management strategy. [ABSTRACT FROM AUTHOR]

Background/Aims: IBD2020 is a global forum for standards of care in inflammatory bowel disease (IBD). The aim of the IBD2020 survey was to identify and describe variations in quality care of IBD. Methods: Patients with IBD from Finland, Italy, France, Canada, Germany, UK, Spain and Sweden were surveyed during 2013 to 2014, covering: disease characteristics; impact on life and work; organization and perceived quality of care. Results: Seven thousand five hundred and seven patients participated (median age, 39 years [range, 10-103 years]; 2,354 male [31.4%]), including 4,097 (54.6%) with Crohn's disease (CD) and 3,410 (45.4%) with ulcerative colitis (UC). Median time from symptom onset to diagnosis was 1 year for both CD (range, 0-47 years) and UC (range, 0-46 years), with no clear evidence of improvement in diagnostic delay over the preceding 24 years. Half of the patients (3,429; 50.0%) rated their care as "excellent" or "very good," with similar results for CD and UC across countries. Five factors were significantly (P <0.01) associated with perceived good quality of care: quality of specialist communication; review consultation being long enough; failure to share information; no access to a dietician; speed of advice. Conclusions: The IBD2020 survey has highlighted areas related to quality of care of IBD from the patients' perspective, with scope for improvement. [ABSTRACT FROM AUTHOR]

Background & Aims: American and European guidelines propose complete endoscopic resection of polypoid dysplasia (adenomas or adenoma-like masses) in patients with longstanding colitis, with close endoscopic follow-up. The incidence of cancer after detection of flat low-grade dysplasia or dysplasia-associated lesion or mass is estimated at 14 cases/1000 years of patient follow-up. However, the risk for polypoid dysplasia has not been determined with precision. We investigated the risk of cancer after endoscopic resection of polypoid dysplasia in patients with ulcerative colitis. Methods: MEDLINE, EMBASE, PubMed, and the Cochrane library were searched for studies of patients with colitis and resected polypoid dysplasia, with reports of colonoscopic follow-up and data on cancers detected. Outcomes from included articles were pooled to provide a single combined estimate of outcomes by using Poisson regression. Results: Of 425 articles retrieved, we analyzed data from 10 studies, comprising 376 patients with colitis and polypoid dysplasia with a combined 1704 years of follow-up. A mean of 2.8 colonoscopies were performed for each patient after the index procedure (range, 0–15 colonoscopies). The pooled incidence of cancer was 5.3 cases (95% confidence interval, 2.7–10.1 cases)/1000 years of patient follow-up. There was no evidence of heterogeneity or publication bias. The pooled rate of any dysplasia was 65 cases (95% confidence interval, 54–78 cases)/1000 patient years. Conclusion: Patients with colitis have a low risk of colorectal cancer after resection of polypoid dysplasia; these findings support the current strategy of resection and surveillance. However, these patients have a 10-fold greater risk of developing any dysplasia than colorectal cancer and should undergo close endoscopic follow-up. [Copyright &y& Elsevier]

Background & Aims: Patients with ulcerative colitis and concomitant primary sclerosing cholangitis (PSC) have a greater risk of developing colorectal dysplasia or invasive cancer than patients with only ulcerative colitis. Therefore, annual surveillance colonoscopies are recommended. We investigated whether primary sclerosing cholangitis is also a risk factor for colorectal dysplasia or cancer in patients with Crohn''s disease of the colon. Methods: We performed a retrospective review of data from a tertiary care hospital on 166 patients with PSC and inflammatory bowel disease; 120 had concomitant ulcerative colitis, 35 had Crohn''s disease, and 11 had indeterminate colitis. The controls comprised 114 patients with colonic involvement of Crohn''s disease and 102 patients with ulcerative colitis. The main outcome parameter was the development of colorectal cancer or intraepithelial neoplasia. Results: Only 1 patient with colonic Crohn''s disease and concomitant PSC developed dysplasia in an adenomatous polyp during a median follow-up of 10 years (range, 7–16 years). In contrast, 2 cancers and 8 cases of colorectal dysplasia were diagnosed in patients with ulcerative colitis and PSC during a median follow up of 11 years (range, 8–16 years); the crude annual incidence of dysplasia or colorectal cancer was 1 in 150 patients with ulcerative colitis. Among patients with colonic Crohn''s disease without PSC, 2 developed colorectal cancer during follow-up. The presence of PSC did not increase the risk of developing colorectal dysplasia in patients with Crohn''s disease (P = 1.00). Conclusions: PSC does not seem to increase the risk for dysplasia of the colon in patients with colonic Crohn''s disease. [Copyright &y& Elsevier]

OBJECTIVES:Acute severe ulcerative colitis (ASC) is a potentially life-threatening disease. We aimed to formulate guidelines for managing ASC in children based on systematic review of the literature and robust consensus process. This manuscript is a product of a joint effort of the ECCO (European Crohn's and Colitis Organization), the Pediatric Porto Inflammatory Bowel Disease (IBD) Working group of ESPGHAN (European Society of Pediatric Gastroenterology, Hepatology, and Nutrition) and ESPGHAN.METHODS:A group of 19 experts in pediatric IBD participated in an iterative consensus process including two face-to-face meetings. A total of 17 predefined questions were addressed by working subgroups based on a systematic review of the literature.RESULTS:The recommendations and practice points were eventually endorsed with a consensus rate of at least 95% regarding: definitions, initial evaluation, standard therapy, timing of second-line therapy, the role of endoscopic evaluation and heparin prophylaxis, how to administer second-line medical therapy, how to assess response, surgical considerations, and discharge recommendations. A management flowchart is presented based on daily scoring of the Pediatric Ulcerative Colitis Activity Index (PUCAI), along with 28 formal recommendations and 34 practice points.CONCLUSIONS:These guidelines provide clinically useful points to guide the management of ASC in children. Taken together, the recommendations offer a standardized protocol that allows effective monitoring of disease progress and timely treatment escalation when needed. [ABSTRACT FROM AUTHOR]

Abstract: Background and aims: Standard practice to maintain remission in ulcerative colitis (UC) consists of daily mesalazine therapy. However, frequent dosing is associated with poor adherence and increased failure rates. The PODIUM (Pentasa™ Once Daily In UC Maintenance) randomised control trial showed 2 g once daily (OD) to be superior to twice daily (BD) dosing for maintaining remission. We sought to determine whether this alternative dosing regimen is cost-effective. Methods: An economic evaluation was conducted to compare costs and outcomes of OD with twice daily (BD) dosing. The main outcome considered was quality-adjusted life years (QALYs) based on health state utilities derived from the primary outcome measure, remission without relapse at 12 months defined by a UCDAI score ≤1. The economic evaluation consisted of two health states: (1) remission and (2) active UC. Results: Annual average treatment costs for OD and BD dosing were £654 (95% CI: £536–£759) and £747 (£620–£860), respectively with an average per person savings of £93 per year. Average annual costs of ancillary care for relapse for OD and BD dosing were £307 (£241–£383) and £396 (£320–£483), respectively. Treatment with OD 2 g mesalazine resulted in an incremental QALY improvement of 0.004 units, indicating that it was the dominant treatment option (i.e. improved outcomes and cost-saving). Variations in parameter estimates in the sensitivity analysis indicated that mesalazine had >0.95 probability of being cost-effective compared to BD based on accepted willingness to pay thresholds applied by the UK National Health Service. Conclusions: Once daily 2 g mesalazine for maintaining remission in UC is cost-saving compared with 1 g twice daily. Cost-savings with 2 g once daily were achieved by differences in ancillary care attributed to higher failure rates observed with 1 g twice daily. [Copyright &y& Elsevier]

Background & Aims: The identification of the association between Crohn’s disease (CD) and NOD2 (CARD15) confirmed both the heritability of CD and highlighted the role of the nuclear factor κB (NFκB) pathway in disease pathogenesis. Other susceptibility loci exist. TUCAN (CARD8) is located beneath a CD peak of linkage on chromosome 19q. TUCAN is expressed in the gut and is a negative regulator of NFκB, making it an excellent candidate gene for gastrointestinal inflammation. Methods: Ten single nucleotide polymorphisms (SNP) across TUCAN were genotyped in 365 controls, 372 patients with CD, and 373 patients with ulcerative colitis. A diagnostic panel for CD was constructed using smoking status and TUCAN, NOD2, IBD5, NOD1, and TNFSF15 data. Results: We demonstrate significant association between a TUCAN SNP and CD (OR 1.35, P = .0083). The association was more pronounced with disease affecting sites other than the colon (odds ratio, 1.52) and NOD2-negative CD (odds ratio, 1.50). Combination of these data with smoking and NOD2, IBD5, NOD1, and TNFSF15 status demonstrated very strong associations with CD and high sensitivities (96.3%), specificities (99.4%), and likelihood ratios (12.8) for CD, although further work will be needed before this model can be translated into direct clinical utility. Conclusions: We have shown an association between a likely functional polymorphism in TUCAN and CD. The combination of these data in a genetic panel suggests that clinicians may soon be able to translate genetic advances into direct benefits for patients. [Copyright &y& Elsevier]

The article reviews the web site gut.bmj.

Abstract: Anti-tumour necrosis factor antagonists have appreciably improved patient outcomes in Crohn''s disease, shifting the goals of treatment from control of symptoms to clinical remission (Crohn''s disease activity index <150) combined with mucosal healing – the new concept of ‘deep remission’. Achieving deep remission brings clinically meaningful benefits, including reduced hospitalization and reduced need for surgery. Aspects such as the dose, timing and intensification of anti-tumour necrosis factor therapy affect the likelihood of achieving deep remission, but definitive evidence on long-term benefits and the risk/benefit profile of treatment intensification is needed. A consequence of the success of anti-tumour necrosis factor therapies has been a change in the disease characteristics of the patient population entering clinical trials. Therefore, new clinical study paradigms, such as cluster randomization and therapeutic strategy trials, are needed. High placebo response rates and the ethics of testing emerging agents against placebo in an era of effective therapies are challenges to traditional randomized controlled trials. Overcoming these challenges will not only help to optimize anti-tumour necrosis factor therapy, but also advance development of emerging treatments for Crohn''s disease. [Copyright &y& Elsevier]

Conventional therapies for ulcerative colitis and Crohn''s disease (CD) include aminosalicylates, corticosteroids, thiopurines, methotrexate, and anti–tumor necrosis factor agents. A time-structured approach is required for appropriate management. Traditional step-up therapy has been partly replaced during the last decade by potent drugs and top-down therapies, with an accelerated step-up approach being the most appropriate in the majority of patients. When patients are diagnosed with CD or ulcerative colitis, physicians should consider the probable pattern of disease progression so that effective therapy is not delayed. This can be achieved by setting arbitrary time limits for administration of biological therapies, changing therapy from mesalamine in patients with active ulcerative colitis, or using rescue therapy for acute severe colitis. In this review, we provide algorithms with a time-structured approach for guidance of therapy. Common mistakes in conventional therapy include overprescription of mesalamine for CD; inappropriate use of steroids (for perianal CD, when there is sepsis, or for maintenance); delayed introduction or underdosing with azathioprine, 6-mercaptopurine, or methotrexate; and failure to consider timely surgery. The paradox of anti–tumor necrosis factor therapy is that although it too is used inappropriately (when patients have sepsis or fibrostenotic strictures) or too frequently (for diseases that would respond to less-potent therapy), it is also often introduced too late in disease progression. Conventional drugs are the mainstay of current therapy for inflammatory bowel diseases, but drug type, timing, and context must be optimized to manage individual patients effectively. [Copyright &y& Elsevier]