Showing papers in "Journal of Crohns & Colitis in 2020"

ECCO Guidelines on Therapeutics in Crohn's Disease: Surgical Treatment

Abstract: This article is the second in a series of two publications relating to the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the management of Crohn's disease. The first article covers medical management; the present article addresses surgical management, including preoperative aspects and drug management before surgery. It also provides technical advice for a variety of common clinical situations. Both articles together represent the evidence-based recommendations of the ECCO for Crohn's disease and an update of previous guidelines.

Are Patients with Inflammatory Bowel Disease at Increased Risk for Covid-19 Infection?

Abstract: Crohn's disease [CD] and ulcerative colitis [UC], the main inflammatory bowel diseases [IBD] in humans, are chronic, immune-inflammatory diseases, the pathogenesis of which suggests a complex interaction between environmental factors and genetic susceptibility. These disabling conditions affect millions of individuals and, together with the drugs used to treat them, can put patients at risk of developing complications and other conditions. This is particularly relevant today, as coronavirus disease [Covid-19] has rapidly spread from China to countries where IBD are more prevalent, and there is convincing evidence that Covid-19-mediated morbidity and mortality are higher in subjects with comorbidities. The primary objectives of this Viewpoint are to provide a focused overview of the factors and mechanisms by which the novel severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infects cells and to illustrate the link between such determinants and intestinal inflammation. We also provide clues about the reasons why the overall IBD population might have no increased risk of developing SARS-CoV-2 infection and highlight the potential of cytokine blockers, used to treat IBD patients, to prevent Covid-driven pneumonia.

Outcomes and Strategies to Support a Treat-to-target Approach in Inflammatory Bowel Disease: A Systematic Review

Abstract: Background and aims Management of Crohn's disease and ulcerative colitis has typically relied upon treatment intensification driven by symptoms alone. However, a 'treat-to-target' management approach may help to address underlying inflammation, minimise disease activity at early stages of inflammatory bowel disease, limit progression, and improve long-term outcomes. Methods A systematic literature review was conducted to identify data relevant to a treat-to-target approach in inflammatory bowel disease, published between January 1, 2007 and May 15, 2017. Results Consistent with recommendations of the Selecting Therapeutic Targets in Inflammatory Bowel Disease [STRIDE] working group, studies have investigated factors influencing the achievement of both endoscopic and histological mucosal healing and patient-level outcomes in inflammatory bowel disease [IBD]. Histological healing and biomarker levels have also been shown to be modifiable outcomes. Although there is a lack of prospectively derived evidence validating mucosal healing as a treatment target, data are emerging to suggest that targeting mucosal healing or inflammation rather than symptoms may be cost-effective in some settings. The review highlighted several strategies that may support the implementation of a treat-to-target approach in IBD. The prospective randomised CALM study demonstrated how tight control [whereby treatment decisions are based on close monitoring of inflammatory biomarkers] leads to improvements in endoscopic and clinical outcomes. The review also considered the influence of coordinated care from a multidisciplinary team and patient engagement with improved adherence, as well as the role of therapeutic drug monitoring in inflammatory bowel disease management. Conclusions A treat-to-target strategy may impact on disease progression and improve outcomes in inflammatory bowel disease. Prospective studies including long-term data are required to ensure that the most appropriate targets and strategies are identified.

IM-UNITI: Three-year Efficacy, Safety, and Immunogenicity of Ustekinumab Treatment of Crohn's Disease.

Abstract: Background and aims Following induction/maintenance treatment in the UNITI/IM-UNITI studies of ustekinumab for Crohn's disease, patients entered a long-term extension for up to 5 years from induction. Efficacy through 152 and safety through 156 weeks are reported. Methods At IM-UNITI Week 44, 567 ustekinumab-treated patients entered the long-term extension and continued to receive blinded subcutaneous ustekinumab on their assigned dose interval, without any subsequent dose adjustment. Placebo-treated patients discontinued after study unblinding [after IM-UNITI Week 44 analyses]. Efficacy data in the long-term extension [LTE] were collected every 12 weeks [q12w] before unblinding and then at q12w/q8w dosing visits. Results Through Week 156, 29.6% of ustekinumab-treated patients discontinued. In an intent-to-treat analysis of randomised patients from IM-UNITI Weeks 0-152, 38.0% of ustekinumab induction responders receiving the drug q12w and 43.0% q8w were in remission at Week 152. Among patients entering the long-term extension in their original randomised groups, 61.9% of q12w and 69.5% of q8w patients were in remission at Week 152. Across all ustekinumab-treated patients [randomised and non-randomised] entering the long-term extension, remission rates at Week 152 were 56.3% and 55.1% for q12w and q8w, respectively. Safety events [per 100 patient-years] were similar among all ustekinumab-treated patients entering the long-term extension and placebo [overall adverse events 389.70 vs 444.17; serious adverse events, 18.97 vs 19.54; serious infections, 4.21 vs 3.97]. Rates of antibodies to ustekinumab through Week 156 remained low, 4.6% in all randomised ustekinumab-treated patients; lowest among patients in the original randomised q8w group [2/82, 2.4%]. Conclusions Continued treatment with subcutaneous ustekinumab maintained clinical response and remission through 3 years in a majority of patients who responded to induction therapy and was well-tolerated. ClinicalTrials.gov number NCT01369355.

Predictors of Primary Response to Biologic Treatment [Anti-TNF, Vedolizumab, and Ustekinumab] in Patients With Inflammatory Bowel Disease: From Basic Science to Clinical Practice.

Abstract: Background Inflammatory bowel diseases [IBD]-ulcerative colitis and Crohn's disease-are commonly treated with biologic drugs. However, only approximately two-thirds of patients have an initial response to these therapies. Personalised medicine has the potential to optimise efficacy, decrease the risk of adverse drug events, and reduce costs by establishing the most suitable therapy for a selected patient. Aim The present study reviews the potential predictors of short-term primary response to biologic treatment, including not only anti-tumour necrosis factor [TNF] agents [such as infliximab, adalimumab, certolizumab, and golimumab] but also vedolizumab and ustekinumab. Methods We performed a systematic bibliographical search to identify studies investigating predictive factors of response to biologic therapy. Results For anti-TNF agents, most of the evaluated factors have not demonstrated usefulness, and many others are still controversial. Thus, only a few factors may have a potential role in the prediction of the response, including disease behaviour/phenotype, disease severity, C-reactive protein, albumin, cytokine expression in serum, previous anti-TNF therapy, some proteomic markers, and some colorectal mucosa markers. For vedolizumab, the availability of useful predictive markers seems to be even lower, with only some factors showing a limited value, such as the expression of α4β7 integrin in blood, the faecal microbiota, some proteomic markers, and some colorectal mucosa markers. Finally, in the case of ustekinumab, no predictive factor has been reported yet to be helpful in clinical practice. Conclusion In summary, currently no single marker fulfils all criteria for being an appropriate prognostic indicator of response to any biologic treatment in IBD.

ECCO Position Paper: Harmonization of the Approach to Ulcerative Colitis Histopathology.

Abstract: Currently, the main targets of drug therapy for ulcerative colitis [UC] are endoscopic and clinical remission. However, there is active discussion about the additional advantages of including histological remission as a target. Accumulating evidence indicates that microscopic activity persists in endoscopically quiescent UC, that histological changes may lag behind clinical remission after treatment, and that absence of histological activity predicts lower rates of relapse, hospitalization, surgery and subsequent neoplasia. Obtaining useful information from mucosal biopsies in this setting depends on accurate and consistent evaluation of histological features. However, there is no standardization of biopsy procedures, histological sample processing technique or histological scoring systems, and there is no agreement on the definitions of histological remission, response or activity. Accordingly, a consensus expert panel convened by the European Crohn's and Colitis Organisation [ECCO] reviewed the literature and agreed a number of position statements regarding harmonization of UC histopathology. The objective was to provide evidence-based guidance for the standardization and harmonization of procedures, definitions and scoring systems for histology in UC, and to reach expert consensus where possible. We propose the absence of intraepithelial neutrophils, erosion and ulceration as a minimum requirement for the definition of histological remission. For randomized control trials we recommend the use of the Robarts histopathology index [RHI] or the Nancy index [NI]. For observational studies or in clinical practice we recommend the use of the NI. To predict the risk of future neoplasia in UC, cumulative histological scores over time are more useful than single scores.

Inflammatory Bowel Disease Care in the COVID-19 Pandemic Era: The Humanitas, Milan, Experience.

Abstract: The outbreak of the COVID-19 caused by coronavirus SARS-CoV2, is rapidly spreading worldwide. This is the first pandemic caused by a coronavirus in history. More than 150 000 confirmed cases worldwide are reported involving the SARS-CoV2, with more than 5000 COVID-19-related deaths on March 14, 2020. Fever, chills, cough, shortness of breath, generalised myalgia, malaise, drowsiness, diarrhoea, confusion, dyspnoea, and bilateral interstitial pneumonia are the common symptoms. No therapies are available, and the only way to contain the virus spread is to regularly and thoroughly clean one's hands with an alcohol-based hand rub or wash them with soap and water, to maintain at least 1 m [3 feet] distance from anyone who is coughing or sneezing, to avoid touching eyes, nose, and mouth, and to stay home if one feels unwell. No data are available on the risk of COVID-19 and outcomes in inflammatory bowel disease [IBD] patients. Outbreak restrictions can impact on the IBD care. We aim to give a viewpoint on how operationally to manage IBD patients and ensure quality of care in the current pandemic era.

Inflammatory Bowel Disease Management During the COVID-19 Outbreak: The Ten Do's and Don'ts from the ECCO-COVID Taskforce.

Abstract: Our knowledge of COVID-19 is changing and evolving rapidly, with novel insights and recommendations, almost on a daily basis. It behooves the medical community to provide updated information on a regular basis, on best practice to facilitate optimal care of infected patients and on appropriate advice for the general population. This is particularly important in the case of patients with chronic conditions, such as inflammatory bowel disease [IBD]. In this review, we have compiled existing evidence on the impact of COVID-19 in IBD patients and provide guidance on the most appropriate care to adopt during the pandemic. Our review highlights that IBD, per se, is not a risk factor for COVID-19. However, all IBD patients with symptoms should be tested for SARS-CoV-2 and the procedures for disease management should be carefully adapted: [i] in SARS-CoV-2-positive IBD patients, medical treatments should be re-evaluated [with a particular focus on corticosteroids] always with the purpose of treating active disease and maintaining remission; [ii] non-urgent surgeries and endoscopic procedures should be postponed for all patients; [iii] online consultancy should be implemented; and [iv] hospitalization and surgery should be limited to life-threatening situations.

A Pilot Integrative Analysis of Colonic Gene Expression, Gut Microbiota, and Immune Infiltration in Primary Sclerosing Cholangitis-Inflammatory Bowel Disease: Association of Disease With Bile Acid Pathways

Abstract: BACKGROUND Although a majority of patients with PSC have colitis [PSC-IBD; primary sclerosing cholangitis-inflammatory bowel disease], this is phenotypically different from ulcerative colitis [UC]. We sought to define further the pathophysiological differences between PSC-IBD and UC, by applying a comparative and integrative approach to colonic gene expression, gut microbiota and immune infiltration data. METHODS Colonic biopsies were collected from patients with PSC-IBD [n = 10], UC [n = 10], and healthy controls [HC; n = 10]. Shotgun RNA-sequencing for differentially expressed colonic mucosal genes [DEGs], 16S rRNA analysis for microbial profiling, and immunophenotyping were performed followed by multi-omic integration. RESULTS The colonic transcriptome differed significantly between groups [p = 0.01]. Colonic transcriptomes from HC were different from both UC [1343 DEGs] and PSC-IBD [4312 DEGs]. Of these genes, only 939 had shared differential gene expression in both UC and PSC-IBD compared with HC. Imputed pathways were predominantly associated with upregulation of immune response and microbial defense in both disease cohorts compared with HC. There were 1692 DEGs between PSC-IBD and UC. Bile acid signalling pathways were upregulated in PSC-IBD compared with UC [p = 0.02]. Microbiota profiles were different between the three groups [p = 0.01]; with inferred function in PSC-IBD also being consistent with dysregulation of bile acid metabolism. Th17 cells and IL17-producing CD4 cells were increased in both PSC-IBD and UC when compared with HC [p < 0.05]. Multi-omic integration revealed networks involved in bile acid homeostasis and cancer regulation in PSC-IBD. CONCLUSIONS Colonic transcriptomic and microbiota analysis in PSC-IBD point toward dysregulation of colonic bile acid homeostasis compared with UC. This highlights important mechanisms and suggests the possibility of novel approaches in treating PSC-IBD.

Neutrophil Extracellular Traps Induce Intestinal Damage and Thrombotic Tendency in Inflammatory Bowel Disease

Abstract: Background and aims Despite the presence of neutrophil extracellular traps [NETs] in inflamed colon having been confirmed, the role of NETs, especially the circulating NETs, in the progression and thrombotic tendency of inflammatory bowel disease [IBD] remains elusive. We extended our previous study to prove that NETs constitute a central component in the progression and prothrombotic state of IBD. Methods In all 48 consecutive patients with IBD were studied. Acute colitis was induced by the treatment of C57BL/6 mice with 3.5% dextran sulphate sodium [DSS] in drinking water for 6 days. Peripheral blood neutrophils and sera were collected from IBD patients and murine colitis models. Exposed phosphatidylserine [PS] was analysed with flow cytometry and confocal microscopy. Procoagulant activity was evaluated using clotting time, purified coagulation complex, and fibrin formation assays. Results We observed higher plasma NET levels and presence of NETs in colon tissue in patients with active IBD. More importantly, NETs were induced in mice with DSS colitis, and inhibition of NET release attenuated colitis as well as colitis-associated tumorigenesis. NET degradation through DNase administration decreased cytokine levels during DSS-induced colitis. In addition, DNase treatment also significantly attenuated the accelerated thrombus formation and platelet activation observed in DSS-induced colitis. NETs triggered PS-positive microparticle release and PS exposure on platelets and endothelial cells partially through TLR2 and TLR4, converting them to a procoagulant phenotype. Conclusions NETs exacerbate colon tissue damage and drive thrombotic tendency during active IBD. Strategies directed against NET formation may offer a potential therapeutic approach for the treatment of IBD.

Inflammatory Bowel Disease in the COVID-19 Pandemic - the Patients' Perspective.

Abstract: BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is affecting lives worldwide The influence of inflammatory bowel disease (IBD) medication and IBD itself on COVID-19 is controversial Additionally, IBD focused guidance is scarce OBJECTIVE: To determine COVID-19 prevalence/exposure, perception and information sources, medication compliance, patient behaviour and physician contact among patients with IBD compared with non-IBD controls METHODS: A cross-sectional anonymous survey of patients with IBD (N=415) at one university IBD clinic and one gastroenterology practice, matched 4:1 with control participants (N=116), was performed RESULTS: Patients with IBD had high fear of infection The fear was more pronounced in patients taking immunosuppressants and it extended to hospitals, private practices and public places, such as supermarkets IBD patients reported leaving their homes less frequently than their peers without IBD A total of 90% of patients with IBD reported washing their hands more frequently Patients taking immunosuppressants were concerned about interactions between medication and COVID-19, whereas patients taking 5-aminosalicylates were not Nonetheless, 964% of patients adhered to continuing their medication Patients sought guidance primarily from television and internet news sites Video consultations were found to be a suitable solution for a subset of patients who are young, have a high level of fear and leave their home less frequently than their peers, whereas overall acceptance of video consultations was limited CONCLUSION: Patients with IBD are significantly more affected by the COVID-19 pandemic than their non-IBD peers, but they continue to adhere to their medication regimens IBD focused COVID-19 information should be actively conveyed

Tofacitinib for rescue therapy in acute severe ulcerative colitis: a real-world experience.

Abstract: Background Acute severe ulcerative colitis is a high stakes event with significant numbers still requiring emergent colectomy, representing a need to establish alternative medical management options. We report a case series of tofacitinib as rescue therapy in biologic-experienced patients with acute severe ulcerative colitis. Methods Four patients were identified over a 1-year period at our institution who initiated tofacitinib for acute severe ulcerative colitis. All four had previously failed at least two biologics, including infliximab, and were failing high-dose oral prednisone therapy before admission. All patients had Mayo disease activity index of at least 10 at admission. After no significant improvement despite receiving a minimum of 3 days of intravenous methylprednisolone and based on elevated Ho and Travis indices at Day 3, patients were offered rescue tofacitinib for induction of remission, or colectomy. Standard induction of tofacitinib was used [10 mg twice daily], and one patient was escalated to 15 mg twice daily after inadequate response. Results All patients experienced improvement in objective symptoms and laboratory markers, and were discharged without colectomy on tofacitinib as maintenance therapy and prednisone taper; 30-day and 90-day colectomy rates on tofacitinib maintenance therapy were zero and 90-day readmission rate was also zero. Two of four patients achieved steroid-free remission on maintenance tofacitinib monotherapy based on clinical symptoms and follow-up endoscopy. No major adverse reaction was reported during induction or maintenance therapy. Conclusions Tofacitinib may be an acceptable rescue agent in biologic-experienced patients with acute severe ulcerative colitis. Tofacitinib may also be safely continued as maintenance therapy once remission has been achieved.

Global Prevalence and Bidirectional Association Between Psoriasis and Inflammatory Bowel Disease-A Systematic Review and Meta-analysis.

Abstract: Background and aims Epidemiological studies have established an association between psoriasis and inflammatory bowel disease [IBD], i.e. ulcerative colitis [UC] and Crohn's disease [CD], but results are inconsistent. The aim of this study was therefore to quantify the prevalences and association between IBD and psoriasis. Methods PubMed, Web of Science, and EMBASE were searched from database inception through April 2018 for studies reporting data on psoriasis among patients with IBD and vice versa. Meta-analysis was performed to estimate, respectively, the prevalences and association between IBD and psoriasis. Data extraction was according to the PRISMA guideline, and quality assessment was made using the Newcastle-Ottawa Scale. The main outcomes were the proportion of psoriasis patients with IBD and vice versa, as well as the association (odds ratio [OR]) of IBD in psoriasis and psoriasis in IBD, respectively. Results Based on quantitative analysis of 93 studies, the prevalence of psoriasis in CD and in UC was 3.6% (95% confidence interval [CI] 3.1%-4.6%) and 2.8% [95% CI 2.0%-3.8%] respectively. The prevalence of CD and UC was 0.7% [95% CI 0.2%-1.3%] and 0.5% [95% CI 0.3%-0.8%], respectively, among patients with psoriasis. Presence of CD or UC was significantly associated with psoriasis, with OR 2.0 [95% CI 1.4-2.9] and OR 1.5 [95% CI 1.2-2.0], respectively. Presence of psoriasis was significantly associated with CD: OR 2.2 [95% CI 1.6-3.1] and with UC: OR 1.6 [95% CI 1.3-2.0]. Conclusions We found significant bidirectional associations between psoriasis and IBD, warranting increased awareness among clinicians in the diagnostic process, especially in children and adolescents with IBD. Last, this study showed an increased frequency of paradoxical psoriasis in patients treated with biologics.

Development of Gut-Selective Pan-Janus Kinase Inhibitor TD-1473 for Ulcerative Colitis: A Translational Medicine Programme.

Abstract: Background and aims Oral systemic pan-Janus kinase [JAK] inhibition is effective for ulcerative colitis [UC] but is limited by toxicities. We describe preclinical to clinical translation of TD-1473-an oral gut-selective pan-JAK inhibitor-from in vitro characterization through a Phase 1b study in patients with UC. Methods TD-1473 JAK inhibition potency was evaluated in vitro; plasma pharmacokinetics, safety and efficacy were assessed in mice. In a first-time-in-human study, plasma pharmacokinetics and safety were assessed after single and multiple [14 days] ascending doses administered orally to healthy subjects. The Phase 1b study randomized patients with moderately to severely active UC to receive once-daily oral TD-1473 20, 80 or 270 mg, or placebo for 28 days. Plasma and colonic tissue concentrations were measured; safety was assessed; and efficacy was evaluated by UC clinical parameters, disease-surrogate biomarkers, endoscopy, histology and colonic tissue JAK signalling. Results TD-1473 exhibited potent pan-JAK inhibitory activity in vitro. Oral TD-1473 administration to mice achieved high, biologically active colonic tissue concentrations with low plasma exposure and decreased oxazolone-induced colitis activity without reducing blood cell counts vs placebo. TD-1473 administration in healthy human subjects and patients with UC yielded low plasma exposure and was generally well tolerated; treatment in patients with UC resulted in biologically active colonic tissue concentrations and descriptive trends toward reduced clinical, endoscopic and histological disease activity vs placebo. Conclusion Gut-selective pan-JAK inhibition with TD-1473 administration resulted in high intestinal vs plasma drug exposure, local target engagement, and trends toward reduced UC disease activity. [Clinicaltrials.gov NCT02657122, NCT02818686].

Dynamics of the Stool Virome in Very Early-Onset Inflammatory Bowel Disease.

Abstract: Background and Aims Dysbiosis of the gut microbiota is a well-known correlate of the pathogenesis of inflammatory bowel disease [IBD]. However, few studies have examined the microbiome in very early-onset [VEO] IBD, which is defined as onset of IBD before 6 years of age. Here we focus on the viral portion of the microbiome—the virome—to assess possible viral associations with disease processes, reasoning that any viruses potentially associated with IBD might grow more robustly in younger subjects, and so be more detectable. Methods Virus-like particles [VLPs] were purified from stool samples collected from patients with VEO-IBD [n = 54] and healthy controls [n = 23], and characterized by DNA and RNA sequencing and VLP particle counts. Results The total number of VLPs was not significantly different between VEO-IBD and healthy controls. For bacterial viruses, the VEO-IBD subjects were found to have a higher ratio of Caudovirales vs to Microviridae compared to healthy controls. An increase in Caudovirales was also associated with immunosuppressive therapy. For viruses infecting human cells, Anelloviridae showed higher prevalence in VEO-IBD compared to healthy controls. Within the VEO-IBD group, higher levels of Anelloviridae DNA were also positively associated with immunosuppressive treatment. To search for new viruses, short sequences enriched in VEO-IBD samples were identified, and some could be validated in an independent cohort, although none was clearly viral; this provides sequence tags to interrogate in future studies. Conclusions These data thus document perturbations to normal viral populations associated with VEO-IBD, and provide a biomarker—Anelloviridae DNA levels—potentially useful for reporting the effectiveness of immunosuppression.

Quality of Care Standards in Inflammatory Bowel Diseases: a European Crohn's and Colitis Organisation [ECCO] Position Paper.

Abstract: The management of inflammatory bowel disease [IBD] is complex, and requires tight control of disease activity, close monitoring to avoid treatment side effects, health care professionals with expertise in IBD, and an interdisciplinary, holistic approach. Despite various efforts to standardise structures, processes, and outcomes,1-8 and due to the high variability at the local, national, and international levels, there are still no clear definitions or outcome measures available to establish quality of care standards for IBD patients which are applicable in all contexts and all countries. For this reason, the European Crohn's and Colitis Organisation [ECCO] supported the construction of a list of criteria summarising current standards of care in IBD. The list comprises 111 quality standard points grouped into three main domains [structure n = 31, process n = 42, outcomes n = 38] and is based on scientific evidence, interdisciplinary expert consensus, and patient-oriented perspectives. The list of proposed criteria is intended to represent the position of ECCO regarding the optimum quality of care that should be available to patients. Since health care systems and regulations vary considerably between countries, this list may require adaptation at local and national levels. It is recognised that not all these criteria that have been identified as optimal will be available in every unit. However, ECCO will continue its efforts to develop and coordinate projects and initiatives that will help to guarantee optimal quality of care for all IBD patients.

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

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

Deficient Resident Memory T Cell and CD8 T Cell Response to Commensals in Inflammatory Bowel Disease.

Abstract: Background Aims: The intestinal microbiota is closely associated with resident memory lymphocytes in mucosal tissue. We sought to understand how acquired cellular and humoral immunity to the microbiota differ in health versus inflammatory bowel disease (IBD). Methods Resident memory T-cells (Trm) in colonic biopsies and local antibody responses to intraepithelial microbes were analyzed. Systemic antigen-specific immune T- and B-cell memory to a panel of commensal microbes was assessed. Results Systemically, healthy blood showed CD4 and occasional CD8 memory T-cell responses to selected intestinal bacteria but few memory B-cell responses. In IBD, CD8 memory T-cell responses decreased although B-cell responses and circulating plasmablasts increased. Possibly secondary to loss of systemic CD8 T-cell responses in IBD, dramatically reduced numbers of mucosal CD8+ Trm and γδ T-cells were observed. IgA responses to intraepithelial bacteria were increased. Colonic Trm expressed CD39 and CD73 ectonucleotidases, characteristic of regulatory T-cells. Cytokines/factors required for Trm differentiation were identified, and in vitro-generated Trm expressed regulatory T-cell function via CD39. Cognate interaction between T-cells and dendritic cells induced T-bet expression in dendritic cells, a key mechanism in regulating cell-mediated mucosal responses. Conclusions A previously unrecognized imbalance exists between cellular and humoral immunity to the microbiota in IBD, with loss of mucosal T-cell-mediated barrier immunity and uncontrolled antibody responses. Regulatory function of Trm may explain their association with intestinal health. Promoting Trm and their interaction with dendritic cells rather than immunosuppression may reinforce tissue immunity, improve barrier function and prevent B-cell dysfunction in microbiota-associated disease and IBD etiology.

The Historical Role and Contemporary Use of Corticosteroids in Inflammatory Bowel Disease.

Abstract: The use of corticosteroids to treat patients with inflammatory bowel disease [IBD] has been the bedrock of IBD therapeutics since the pioneering work of Truelove and Witts in the UK in the 1950s and subsequent large cohort studies in the USA and Europe. Nevertheless, although effective for induction of remission, these agents do not maintain remission and are associated with a long list of recognised side effects, including a risk of increased mortality. With the arrival of an increasing number of therapies for patients with IBD, the question arises as to whether we are using these agents appropriately in contemporary practice. This review discusses the historical background to steroid usage in IBD, and also provides a brief review of the literature on side effects of corticosteroid treatment as relevant to IBD patients. Data on licensed medications are presented with specific reference to the achievement of corticosteroid-free remission. We review available international data on the incidence of corticosteroid exposure and excess, and discuss some of the observations we and others have made concerning health care and patient-level factors associated with the risk of corticosteroid exposure, including identification of 'at-risk' populations.

Efficacy of JAK inhibitors in Crohn's Disease

Abstract: Inhibition of Janus kinases [JAKs] in Crohn's disease [CD] patients has shown conflicting results in clinical trials. Tofacitinib, a pan-JAK inhibitor, showed efficacy in ulcerative colitis [UC] and has been approved for the treatment of patients with moderate to severe UC. In contrast, studies in CD patients were disappointing and the primary end point of clinical remission could not be met in the respective phase II induction and maintenance trials. Subsequently, the clinical development of tofacitinib was discontinued in CD. In contrast, efficacy of filgotinib, a selective JAK1 inhibitor, in CD patients was demonstrated in the randomized, double-blinded, placebo-controlled phase II FITZROY study. Upadacitinib also showed promising results in a phase II trial in moderate to severe CD. Subsequently, phase III programmes in CD have been initiated for both substances, which are still ongoing. Several newer molecules of this class of orally administrated immunosuppressants are being tested in clinical programmes. The concern of side effects of systemic JAK inhibition is addressed by either exclusively intestinal action or higher selectivity [Tyk2 inhibitors]. In general, JAK inhibitors constitute a new promising class of drugs for the treatment of CD.

The Safety Profile of Vedolizumab in Ulcerative Colitis and Crohn's Disease: 4 Years of Global Post-marketing Data.

Abstract: BACKGROUND AND AIMS Vedolizumab is a gut-selective antibody to α 4 β 7 integrin, approved to treat moderate-to-severe ulcerative colitis and Crohn's disease in adults. Clinical trial data on patients meeting protocol-specified criteria may not reflect real-world clinical practice. This is a descriptive analysis of 4 years of post-marketing safety data on vedolizumab. METHODS The Vedolizumab Global Safety Database contains all adverse event reports collated by Takeda Pharmaceutical Company Ltd since vedolizumab approval [May 20, 2014]. Adverse event reports received between approval and May 19, 2018 were identified using Medical Dictionary for Regulatory Activities version 21.0 Preferred Terms. Adverse event frequencies were calculated and categorised. RESULTS In approximately 208 050 patient-years of vedolizumab exposure, 32 752 patients reported 80 218 events. In patients with Crohn's disease or ulcerative colitis, 37 662 and 34 259 events occurred in 14 191 and 14 042 patients, respectively, and 8297 events occurred in 4519 individuals with other [off-label] or unreported indications. Overall, 5230 [14%; Crohn's disease] and 3580 [10%; ulcerative colitis] events were serious. Most frequently reported were gastrointestinal events (Crohn's disease, 6156 [16%]; ulcerative colitis, 5701 [17%]). Patients with Crohn's disease or ulcerative colitis reported 251 malignancies [<1%], 402 hepatobiliary events [<1%], and 5876 infections (1137 serious [19%], 301 opportunistic [5%]). Patients aged ≥70 years [2326 patients] reported <10% of events. CONCLUSIONS Adverse event patterns were consistent with clinical trials, with no new safety concerns. Most reported events were non-serious and event frequency was low, considering patient-years of exposure. Although limitations of post-marketing safety reports require acknowledgement, these real-world data support a favourable safety profile of vedolizumab.

Ustekinumab for Extra-intestinal Manifestations of Inflammatory Bowel Disease: A Systematic Literature Review.

Abstract: BACKGROUND AND AIMS Extra-intestinal manifestations [EIMs] are frequent in patients with inflammatory bowel diseases [IBD] and are challenging conditions to manage. Tumour necrosis factor alpha antagonists [anti-TNFα] are recognised as the primary therapeutic option. We aimed to summarise evidence on the efficacy of ustekinumab for the treatment of EIMs. METHODS We searched in PubMed, Cochrane Library, and Web of Science, up to October 2020, all interventional and non-interventional studies published in English and assessing ustekinumab efficacy for the treatment of EIMs. RESULTS Nine studies [eight retrospective and one prospective] were included, enrolling a total of 254 patients with IBD and EIM. Ustekinumab showed its effectiveness for arthralgia and psoriatic arthritis in 152 patients through three high-quality studies. Conversely, no efficacy was found in axial spondyloarthritis. Psoriasis, pyoderma gangrenosum, and erythema nodosum were assessed in seven studies including 65 patients and showed high response rate to ustekinumab treatment. Promising results for aphthous stomatitis and uveitis were reported, but data were limited to 20 patients from two studies. CONCLUSIONS Ustekinumab showed to be an effective option for the treatment of EIMs, especially for dermatological and rheumatological manifestations. However, more data are needed to confirm the role of ustekinumab in this setting.

Perioperative Dietary Therapy in Inflammatory Bowel Disease

Abstract: BACKGROUND AND AIMS: The incidence of inflammatory bowel disease [IBD] is rising worldwide and no cure is available. Many patients require surgery and they often present with nutritional deficiencies. Although randomised controlled trials of dietary therapy are lacking, expert IBD centres have long-established interdisciplinary care, including tailored nutritional therapy, to optimise clinical outcomes and resource utilisation. This topical review aims to share expertise and offers current practice recommendations to optimise outcomes of IBD patients who undergo surgery. METHODS: A consensus expert panel consisting of dietitians, surgeons, and gastroenterologists, convened by the European Crohn's and Colitis Organisation, performed a systematic literature review. Nutritional evaluation and dietary needs, perioperative optimis ation, surgical complications, long-term needs, and special situations were critically appraised. Statements were developed using a Delphi methodology incorporating three successive rounds. Current practice positions were set when ≥80% of participants agreed on a recommendation. RESULTS: A total of 26 current practice positions were formulated which address the needs of IBD patients perioperatively and in the long term following surgery. Routine screening, perioperative optimisation by oral, enteral, or parenteral nutrition, dietary fibre, and supplements were reviewed. IBD-specific situations, including management of patients with a restorative proctocolectomy, an ostomy, strictures, or short-bowel syndrome, were addressed. CONCLUSIONS: Perioperative dietary therapy improves the outcomes of IBD patients who undergo a surgical procedure. This topical review shares interdisciplinary expertise and provides guidance to optimise the outcomes of patients with Crohn's disease and ulcerative colitis. taking advantage of contemporary nutrition science.

The TLR9 Agonist Cobitolimod Induces IL10-Producing Wound Healing Macrophages and Regulatory T Cells in Ulcerative Colitis

Abstract: BACKGROUND AND AIMS The topically applied Toll-like receptor 9 [TLR9] agonist cobitolimod is a first-in-class DNA-based oligonucleotide with demonstrated therapeutic efficacy in clinical trials with ulcerative colitis [UC] patients. We here characterized its anti-inflammatory mechanism in UC. METHODS Luminal cobitolimod administration was evaluated in an experimental dextran sodium sulfate [DSS]-induced colitis model. Cultured blood and mucosal cells from UC patients were treated with cobitolimod and analysed via microarray, quantitative real-time PCR, ELISA and flow cytometry. Intestinal slides of cobitolimod-treated UC patients were analysed by immunohistochemistry. RESULTS Cobitolimod administration markedly suppressed experimental colitis activity, and microarray analyses demonstrated mucosal IL10 upregulation and suppression of IL17 signalling pathways. Cobitolimod treatment was associated with significant induction of mucosal IL10+Tr1 and Treg cells and suppression of Th17 cells. TLR9 knockout mice indicated that cobitolimod requires TLR9 signalling for IL10 induction. In UC patients, mucosal TLR9 levels correlated with severity of inflammation. Cobitolimod inhibited IL17A and IL17F, but increased IL10 and FoxP3 expression in cultured intestinal UC T cells. Cobitolimod-mediated suppression of intestinal IL17+T cells was abrogated by IL10 blockade. Furthermore, cobitolimod led to heightened IL10 production by wound healing macrophages. Immunohistochemistry in intestinal biopsies of cobitolimod-treated UC patients indicated increased presence of IL10+mononuclear and regulatory T cells, as well as reduction of IL17+cells. CONCLUSION Activation of TLR9 via cobitolimod might represent a novel therapeutic approach in UC, as it suppresses Th17 cells and induces anti-inflammatory IL10+macrophages and regulatory T cells, thereby modifying the dysregulated intestinal cytokine balance. PODCAST This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.

Highly Bioavailable Curcumin Derivative Ameliorates Crohn’s Disease Symptoms: A Randomized, Double-Blind, Multicenter Study

Abstract: Background & aims The new curcumin derivative Theracurmin® has a 27-fold higher absorption rate than natural curcumin powder. Theracurmin® is an inhibitor of nuclear factor-κB, which mediates the expression of inflammatory cytokines. The effect of Theracurmin® on inflammatory bowel disease in humans has not been explored; therefore, we investigated the efficacy and safety of Theracurmin® in patients with Crohn's disease. Methods In this randomized, double-blinded study performed at 5 independent medical centers in Japan, Theracurmin® (360 mg/day, n=20) or placebo (n=10) was administered to patients with active mild-to-moderate Crohn's disease for 12 weeks. The agent's efficacy was assessed by evaluating clinical and endoscopic remission, healing of anal lesions, and blood levels of inflammatory markers. Results In the Theracurmin® group, a significant reduction in clinical disease activity was observed in week 12 relative to that in week 0 (P=0.005). On intention-to-treat analysis, clinical remission rates were 35%, 40%, and 40% at weeks 4, 8, and 12, respectively, which were significantly higher than those in the placebo group (all 0%; P=0.033, P=0.020, and P=0.020, respectively). Furthermore, reduction in endoscopic Crohn's disease severity (P=0.032) was observed at week 12 in the Theracurmin® group. The endoscopic remission rates were 15% and 0% in the Theracurmin® and placebo groups, respectively. Significant healing of anal lesions (P=0.017) was observed at week 8 in the Theracurmin® group. No serious adverse events were observed in either group throughout the study. Conclusions Theracurmin® shows significant clinical and endoscopic efficacy together with a favorable safety profile in patients with active mild-to-moderate Crohn's disease.

Systematic Review: Gastrointestinal Ultrasound Scoring Indices for Inflammatory Bowel Disease.

Abstract: Background and aims Serial measurements of luminal disease activity may facilitate inflammatory bowel disease management. Gastrointestinal ultrasound is an easily performed, non-invasive alternative to other assessment modes. However, its widespread use is limited by concerns regarding validity, reliability, and responsiveness. We systematically identified ultrasound scoring indices used to evaluate inflammatory bowel disease activity and examine their operating characteristics. Methods Electronic databases were searched from inception to June 14, 2019 using pre-defined terms. Studies that reported on gastrointestinal ultrasound index operating properties in an inflammatory bowel disease population were eligible for inclusion. Study characteristics, index components, and operating property (i.e., validity, reliability, responsiveness, sensitivity, specificity, accuracy, positive predictive value, and negative predictive value) data were extracted. The QUADAS-2 tool was used to examine study-level risk of bias. Results Of the 2610 studies identified, 26 studies reporting on 21 ultrasound indices were included. The most common index components included bowel wall thickness, colour Doppler imaging, and bowel wall stratification. The correlation between ultrasound indices and references standards ranged from r=0.62-0.95 and k=0.40-0.96. Sensitivity, specificity, accuracy, positive predictive value, and negative predictive values ranged from 39%-100%, 63%-100%, 73%-100%, 57%-100%, and 40%-100%, respectively. Reliability and responsiveness data were limited. Most (92%, 24/26) studies received at least one unclear or high risk of bias rating. Conclusions Several gastrointestinal ultrasound indices for use in inflammatory bowel disease have been developed. Future research should focus on fully validating existing or novel gastrointestinal ultrasound scoring instruments for assessment of Crohn's disease and ulcerative colitis.

Intestinal epithelial cells express immunomodulatory ISG15 during active ulcerative colitis and Crohn's disease.

Abstract: Background and aims Intestinal epithelial cells [IECs] secrete cytokines that recruit immune cells to the mucosa and regulate immune responses that drive inflammation in inflammatory bowel disease [IBD]. However, experiments in patient-derived IEC models are still scarce. Here, we aimed to investigate how innate immunity and IEC-specific pattern recognition receptor [PRR] signalling can be involved in an enhanced type I interferon [IFN] gene signature observed in colon epithelium of patients with active IBD, with a special focus on secreted ubiquitin-like protein ISG15. Methods Gene and protein expression in whole mucosa biopsies and in microdissected human colonic epithelial lining, in HT29 human intestinal epithelial cells and primary 3D colonoids treated with PRR-ligands and cytokines, were detected by transcriptomics, in situ hybridisation, immunohistochemistry, western blots, and enzyme-linked immunosorbent assay [ELISA]. Effects of IEC-secreted cytokines were examined in human peripheral blood mononuclear cells [PBMCs] by multiplex chemokine profiling and ELISA. Results The type I IFN gene signature in human mucosal biopsies was mimicked in Toll-like receptor TLR3 and to some extent tumour necrosis factor [TNF]-treated human IECs. In intestinal biopsies, ISG15 expression correlated with expression of the newly identified receptor for extracellular ISG15, LFA-1 integrin. ISG15 was expressed and secreted from HT29 cells and primary 3D colonoids through both JAK1-pSTAT-IRF9-dependent and independent pathways. In experiments using PBMCs, we show that ISG15 releases IBD-relevant proinflammatory cytokines such as CXCL1, CXCL5, CXCL8, CCL20, IL1, IL6, TNF, and IFNγ. Conclusions ISG15 is secreted from primary IECs upon extracellular stimulation, and mucosal ISG15 emerges as an intriguing candidate for immunotherapy in IBD.

A Diversified Dietary Pattern Is Associated With a Balanced Gut Microbial Composition of Faecalibacterium and Escherichia/Shigella in Patients With Crohn's Disease in Remission

Abstract: BACKGROUND AND AIMS Crohn's disease [CD] is associated with alterations in gut microbial composition and function. The present controlled-intervention study investigated the relationship between patterns of dietary intake and baseline gut microbiota in CD patients in remission and examined the effects of a dietary intervention in patients consuming a non-diversified diet [NDD]. METHODS Forty outpatients with quiescent CD were recruited in Calgary, Alberta, Canada. Based on 3-day food records, patients consuming a lower plant-based and higher red and processed meat-based diet were assigned to the NDD group [n = 15] and received a 12-week structured dietary intervention; all other patients were assigned to the diversified diet [DD] control group [n = 25] and received conventional management. Faecal microbiota composition, short chain fatty acids [SCFAs] and calprotectin were measured. RESULTS At baseline the NDD and DD groups had a different faecal microbial beta-diversity [p = 0.003, permutational multivariate analysis of variance]. The NDD group had lower Faecalibacterium and higher Escherichia/Shigella relative abundances compared to the DD group [3.3 ± 5.4% vs. 8.5 ± 10.6%; 6.9 ± 12.2% vs. 1.6 ± 4.4%; p ≤ 0.03, analysis of covariance]. These two genera showed a strong negative correlation [rs = -0.60, q = 0.0002]. Faecal butyrate showed a positive correlation with Faecalibacterium [rs = 0.52, q = 0.002], and an inhibitory relationship with Escherichia/Shigella abundance [four-parameter sigmoidal model, R = -0.83; rs = -0.44, q = 0.01], respectively. After the 12 weeks of dietary intervention, no difference in microbial beta-diversity between the two groups was observed [p = 0.43]. The NDD group demonstrated an increase in Faecalibacterium [p < 0.05, generalized estimated equation model], and resembled the DD group at the end of the intervention [p = 0.84, t-test with permutation]. We did not find an association of diet with faecal SCFAs or calprotectin. CONCLUSIONS Dietary patterns are associated with specific gut microbial compositions in CD patients in remission. A diet intervention in patients consuming a NDD modifies gut microbial composition to resemble that seen in patients consuming a DD. These results show that diet is important in shaping the microbial dysbiosis signature in CD towards a balanced community.

Immunomodulatory Effect of Urine-derived Stem Cells on Inflammatory Bowel Diseases via Downregulating Th1/Th17 Immune Responses in a PGE2-dependent Manner.

Abstract: Background and aims Despite the therapeutic promise of stem cell therapy in the treatment of inflammatory bowel diseases [IBD], most donor cell populations have to be obtained via invasive approaches and often remain insufficiently validated. Urine-derived stem cells [USC] were recently shown to have regenerative properties and can be harvested in a safe, low-cost, and noninvasive way. This study aims to evaluate the immunomodulatory effect of USC and their efficacy in the management of IBD. Methods Human USC were isolated and expanded from the urine of healthy male adult volunteers [n = 3, age range 24-30 years]. USC were characterised by cell surface marker expression profile and multipotent differentiation. The in vitro immunomodulatory effect of USC was evaluated by co-culturing with human CD4+ T cells upon stimulation with phytohaemagglutinin [PHA]. The proliferation of CD4+ T was measured by fluorescence-activated cell sorting [FACS]. Cytokine array and quantitative real-time polymerase chain reaction [RT-PCR] were applied to examine cytokine levels. In vivo therapeutic value of USC was assessed using a murine colitis model induced by dextran sulphate sodium [DSS] or 2, 4, 6-trinitrobenzene sulphonic acid [TNBS]. The immunomodulatory effect of USC and bone marrow-derived mesenchymal stem cells [BMSC] was compared when co-cultured with CD4+ T cells. The therapeutic efficacy of USC and BMSC on IBD was compared when administered in an acute DSS model in vivo. Results USC were positive for mesenchymal stem cell markers but were negative for haematopoietic stem cell markers. These cells differentiated into osteo-, adipo-, and chondrogenic cell lineages. Similar to BMSC, the proliferation of CD4+ T cells was significantly inhibited when co-cultured with USC, as a consequence of Th1/Th17 immune response inhibition. Systemic administration of USC significantly ameliorated the clinical and histopathological severity of colitis and increased the survival rate in both acute and chronic murine colitis models. Moreover, implantation of USC led to downregulation of the Th1/Th17 immune responses in a PGE2-dependent manner. Conclusions This study demonstrated that implantation of USC reduces inflammation in an IBD rodent model via downregulation of Th1/Th17 immune responses, indicating that USC therapy serves as a potential cell-based therapeutic candidate treatment for IBD.

Combined Biologic and Immunomodulatory Therapy is Superior to Monotherapy for Decreasing the Risk of Inflammatory Bowel Disease-Related Complications.

Abstract: Background and aims The combination of infliximab and azathioprine is more efficacious than either therapy alone for Crohn's disease [CD] and ulcerative colitis [UC]. However, it is uncertain whether these benefits extend to real-world clinical practice and to other combinations of biologics and immunomodulators. Methods We collected health administrative data from four Canadian provinces representing 78 413 patients with inflammatory bowel disease [IBD] of whom 11 244 were prescribed anti-tumour necrosis factor [anti-TNF] agents. The outcome of interest was the first occurrence of treatment failure: an unplanned IBD-related hospitalization, IBD-related resective surgery, new/recurrent corticosteroid use or anti-TNF switch. Multivariable Cox proportional hazards modelling was used to assess the association between the outcome of interest and receiving combination therapy vs anti-TNF monotherapy. Multivariable regression models were used to assess the impact of choice of immunomodulator or biologic on reaching the composite outcome, and random effects generic inverse variance meta-analysis of deterministically linked data was used to pool the results from the four provinces to obtain aggregate estimates of effect. Results In comparison with anti-TNF monotherapy, combination therapy was associated with a significant decrease in treatment ineffectiveness for both CD and UC (CD: adjusted hazard ratio [aHR] 0.77, 95% confidence interval [CI] 0.66-0.90; UC: aHR 0.72, 95% CI 0.62-0.84). Combination therapy was equally effective for adalimumab and infliximab in CD. In UC azathioprine was superior to methotrexate as the immunomodulatory agent (aHR = 1.52 [95% CI 1.02-2.28]) but not CD (aHR = 1.22 [95% CI 0.96-1.54]). Conclusion In an analysis of a database of real-world patients with IBD, combination therapy decreased the likelihood of treatment failure in both CD and UC.