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SummaryClinical benefits to cytokine blockade in ileal Crohn’s disease (iCD) have been limited to a subset of patients. Whether cellular and molecular heterogeneity contributes to variability in treatment responses has been unclear. Using single cell technologies combining scRNAseq, CyTOF and multiplex tissue imaging, we mapped the cellular landscape of inflamed ileum lesions, adjacent non-inflamed ileum and matched circulating blood cells of iCD patients. In inflamed tissues, we identified a pathogenic module characterized by an inflammatory mononuclear phagocyte (Inf.MNP)-associated cellular response organized around inflammatory macrophages and mature dendritic cells in a subset of iCD patients. We confirmed the Inf.MNP-associated cellular response in 4 independent iCD cohorts (n=441) and showed that presence of this pathogenic module at diagnosis correlated with primary resistance to anti-TNF therapy. Single cell mapping of iCD tissues identifies a complex cellular signature of anti-TNF resistance thereby revealing novel biomarkers of treatment response and tailored therapeutic opportunities.

Background Vedolizumab (VDZ), a gut-selective anti-lymphocyte trafficking monoclonal anti-a4β7-integrin antibody, has showed efficacy in multiple phase 3 clinical trials in patients (pts) with inflammatory bowel disease (IBD). Decreased likelihood of response to adalimumab was previously observed with concomitant 5-ASA.1 This post-hoc analysis assessed the impact of concomitant 5-ASA on efficacy and safety in VDZ-treated pts with IBD. Methods Pts with IBD treated with VDZ intravenous (IV) or subcutaneous (SC) in phase 3 trials who continued 5-ASA (at any dose) at the time of starting VDZ were compared with those who received no concomitant 5-ASA. Pts were also stratified by ulcerative colitis (UC) or Crohn’s disease (CD). Efficacy outcomes were the proportion of pts achieving clinical response, clinical remission and corticosteroid (CS)-free clinical remission at Wk 6 (end of induction phase) and Wk 52 (end of maintenance phase). Safety outcomes were the proportion of pts experiencing any infection and enteric infections. Studies included: GEMINI 1 and 2, and VISIBLE 1 and 2 in efficacy analyses; GEMINI 1, 2, 3 and long-term safety for VDZ IV, and VISIBLE 1, 2, and open-label extension (data cut-off 17 May 2019) for VDZ SC in safety analyses. Results At Wk 6, clinical response was achieved by 191 (70.0%) and 69 (61.6%) VDZ-treated pts with UC with and without 5-ASA, respectively, and by 139 (64.4%) and 161 (57.7%) pts with CD, respectively (Table 1). At week 52, clinical remission was achieved by 134 (46.0%) and 45 (38.8%) VDZ-treated pts with UC with or without 5-ASA, and by 116 (50.2%) and 132 (37.5%) pts with CD, respectively. CS-free clinical remission at Wk 52 was achieved by 55 (34.8%) and 19 (37.3%) VDZ-treated pts with UC with and without 5-ASA, respectively, and by 46 (41.4%) and 46 (31.5%) pts with CD, respectively. Multivariate analysis in general showed no differences in VDZ efficacy with or without 5-ASA. No new safety issues or signals were identified. A tendency towards lower incidence of all infections and enteric infections was observed in pts receiving VDZ (IV or SC) with versus without 5-ASA (Table 2). Conclusion In this post-hoc analysis of VDZ pivotal trial data, concomitant 5-ASA does not appear to significantly impact the efficacy of VDZ in pts with IBD. No new safety signals were identified. The safety profile of VDZ IV and SC, with and without 5-ASA was consistent with the known safety profile of VDZ. Although there was limited data in some subgroups, there was no evidence to suggest that concomitant 5-ASA usage was associated with higher infection rates. These data will be useful to inform risk-benefit assessments of continued 5-ASA in VDZ-treated pts. Reference

Background Histological assessment is becoming increasingly important in the management of Ulcerative Colitis (UC). The Nancy index (NI), a recently developed and validated score, has been shown to accurately represent histological inflammation and to correlate with prognosis. However, it is a composite score, involving the analysis of more than one histological feature, which may limit its applicability. Our aim was to evaluate if a single component of the NI could individually predict prognosis in limited UC (E1 and E2) patients. Methods Multi-centre retrospective cohort study of newly diagnosed, treatment-naïve proctitis and left-sided ulcerative colitis patients. Biopsies from inflamed rectal mucosa were reviewed by two pathologists. Histological features from the NI were selected for analysis, including presence of ulcers, acute inflammatory infiltrate (with separate evaluation of neutrophils in lamina propria and epithelium) and chronic inflammatory infiltrate. Mucin depletion and basal plasmacytosis were also evaluated. The primary outcome was a composite outcome intended to evaluate disease-related complications, including proximal disease extension, need for hospitalisation or colectomy. Survival analysis, including univariate and multivariate Cox-regression analysis was performed. Results A total of 91 patients were included (56.0% males, mean age 44±17 years, median follow-up 44 months [2–328]). Overall, 64.8% of the patients had proctitis (E1) and 35.2% left-sided colitis (E2). The most frequent histological features were the presence of chronic inflammatory infiltrate (93.4%), mucin depletion (81.3%) and basal plasmacytosis (78.0%). During the follow-up, 22.0% presented a disease-related complication. The NI was not able to predict prognosis (HR 3.09, 95% CI 0.71–13.36, p=0.132). In univariate analysis, the presence of neutrophils in the epithelium in more than 50% of the crypts was marginally significant for the primary outcome (HR 2.51, 95% CI 0.99–6.36, p=0.05). In multivariate analysis, after adjusting for gender, age at diagnosis, disease extent (E1 vs E2), Mayo endoscopic score (< 2 vs ≥ 2) and clinical severity at diagnosis (mild vs moderate to severe UC) this single component of the score was associated with the primary outcome (aHR 3.36, 95% IC 1.21–9.31, p=0.02). No other histological feature was able to individually predict prognosis (p>0.05). Conclusion The presence of neutrophils in the epithelium in more than 50% of the crypts in endoscopically inflamed mucosa at diagnosis was associated with higher disease complications in limited UC patients. The evaluation of a single feature could facilitate the use of histology in the prediction of prognosis in UC. Our results need to be prospectively validated.

The coronavirus disease 2019 (COVID-19) pandemic caused by the highly infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents most often with mild clinical symptoms, but the severe forms are of major concern.1 SARS-CoV-2 enters human cells via the angiotensin-converting enzyme 2 receptor, expressed on epithelial and endothelial cells.2 Because the highest angiotensin-converting enzyme 2 expression is in the terminal ileum and colon, and up-regulated further during inflammation, and many COVID-19 patients experience gastrointestinal symptoms, longitudinal data are necessary to determine whether inflammatory bowel disease (IBD) patients are at risk for severe or complicated COVID-19. A recent analysis in IBD patients from the Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) registry showed older age, steroid medication, and comorbidities as risk factors for severe evolution, and the same study showed that the 29 IBD patients younger than age 20 had only mild disease courses.3 This report describes the disease course of COVID-19 in an expanded sample of pediatric IBD patients from 2 international databases.

Background & aimsWe created and validated a clinical decision support tool (CDST) to predict outcomes of vedolizumab therapy for ulcerative colitis (UC).MethodsWe performed logistic regression analyses of data from the GEMINI 1 trial, from 620 patients with UC who received vedolizumab induction and maintenance therapy (derivation cohort), to identify factors associated with corticosteroid-free remission (full Mayo score of 2 or less, no subscore above 1). We used these factors to develop a model to predict outcomes of treatment, which we called the vedolizumab CDST. We evaluated the correlation between exposure and efficacy. We validated the CDST in using data from 199 patients treated with vedolizumab in routine practice in the United States from May 2014 through December2017.ResultsAbsence of exposure to a tumor necrosis factor (TNF) antagonist (+3 points), disease duration of 2 y or more (+3 points), baseline endoscopic activity (moderate vs severe) (+2 points), and baseline albumin concentration (+0.65 points per 1 g/L) were independently associated with corticosteroid-free remission during vedolizumab therapy. Patients in the derivation and validation cohorts were assigned to groups of low (CDST score, 26 points or less), intermediate (CDST score, 27-32 points), or high (CDST score, 33 points or more) probability of vedolizumab response. We observed a statistically significant linear relationship between probability group and efficacy (area under the receiver operating characteristic curve, 0.65), as well as drug exposure (P < .001) in the derivation cohort. In the validation cohort, a cutoff value of 26 points identified patients who did not respond to vedolizumab with high sensitivity (93%); only the low and intermediate probability groups benefited from reducing intervals of vedolizumab administration due to lack of response (P = .02). The vedolizumab CDST did not identify patients with corticosteroid-free remission during TNF antagonist therapy.ConclusionsWe used data from a trial of patients with UC to develop a scoring system, called the CDST, which identified patients most likely to enter corticosteroid-free remission during vedolizumab therapy, but not anti-TNF therapy. We validated the vedolizumab CDST in a separate cohort of patients in clinical practice. The CDST identified patients most likely to benefited from reducing intervals of vedolizumab administration due to lack of initial response. ClinicalTrials.gov no: NCT00783718.

Prior studies suggest that medication exposures may be associated with new onset inflammatory bowel disease (IBD). The aim of this study was to determine the effect of statins on the risk of new onset IBD in a large United States health claims database.We conducted a retrospective matched case-control study with a national medical claims and pharmacy database from Source Healthcare Analytics LLC. We included any patient aged 18 or older with ICD-9 code 555.x for Crohn's disease (CD) or 556.x for ulcerative colitis (UC) between January 2008 and December 2012. IBD patients diagnosed in 2012 were compared with the age group, gender, race, and geographically matched controls. Controls had no ICD-9 codes for CD, UC, or IBD-associated diseases and no prescriptions for IBD-related medications. New onset IBD patients were defined as having at least three separate CD or UC ICD-9 codes and no IBD-related ICD-9 or prescription before first IBD ICD-9. Statin exposure was assessed by Uniform System of Classification level 5 code. To account for diagnostic delay, exposures within 6 months of first ICD-9 were excluded. Exposures within 12 and 24 months were excluded in sensitivity analyses. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for new onset IBD, CD, and UC.A total of 9,617 cases and 46,665 controls were included in the analysis. Any statin exposure was associated with a significantly decreased risk of IBD (OR 0.68, 95% CI 0.64-0.72), CD (0.64, 95% CI 0.59-0.71), and UC (OR 0.70, 95% CI 0.65-0.76). This effect was similar for most specific statins and regardless of intensity of therapy. The protective effect against new onset CD was strongest among older patients. Statins' association with a lower risk of IBD was similar after adjusting for antibiotics, hormone replacement therapy, oral contraceptives, comorbidities, and cardiovascular medications.Statins may have a protective effect against new onset IBD, CD, and UC. This decreased risk is similar across most statins and appears to be stronger among older patients, particularly in CD.

Ruane et al. demonstrate a role for the microbiota in modulating protective immunity to intranasal vaccination via the ability of lung dendritic cells to induce B cell IgA class switching., Protective immunoglobulin A (IgA) responses to oral antigens are usually orchestrated by gut dendritic cells (DCs). Here, we show that lung CD103+ and CD24+CD11b+ DCs induced IgA class-switch recombination (CSR) by activating B cells through T cell–dependent or –independent pathways. Compared with lung DCs (LDC), lung CD64+ macrophages had decreased expression of B cell activation genes and induced significantly less IgA production. Microbial stimuli, acting through Toll-like receptors, induced transforming growth factor-β (TGF-β) production by LDCs and exerted a profound influence on LDC-mediated IgA CSR. After intranasal immunization with inactive cholera toxin (CT), LDCs stimulated retinoic acid–dependent up-regulation of α4β7 and CCR9 gut-homing receptors on local IgA-expressing B cells. Migration of these B cells to the gut resulted in IgA-mediated protection against an oral challenge with active CT. However, in germ-free mice, the levels of LDC-induced, CT–specific IgA in the gut are significantly reduced. Herein, we demonstrate an unexpected role of the microbiota in modulating the protective efficacy of intranasal vaccination through their effect on the IgA class-switching function of LDCs.

Background and Aims The impact of Coronavirus disease 2019 (COVID-19) on patients with inflammatory bowel disease (IBD) is unknown. We sought to characterize the clinical course of COVID-19 among patients with IBD and evaluate the association among demographics, clinical characteristics, and immunosuppressant treatments on COVID-19 outcomes. Methods Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) is a large, international registry created to monitor outcomes of patients with IBD with confirmed COVID-19. We calculated age-standardized mortality ratios and used multivariable logistic regression to identify factors associated with severe COVID-19, defined as intensive care unit admission, ventilator use, and/or death. Results 525 cases from 33 countries were reported (median age 43 years, 53% men). Thirty-seven patients (7%) had severe COVID-19, 161 (31%) were hospitalized, and 16 patients died (3% case fatality rate). Standardized mortality ratios for patients with IBD were 1.8 (95% confidence interval [CI], 0.9–2.6), 1.5 (95% CI, 0.7–2.2), and 1.7 (95% CI, 0.9–2.5) relative to data from China, Italy, and the United States, respectively. Risk factors for severe COVID-19 among patients with IBD included increasing age (adjusted odds ratio [aOR], 1.04; 95% CI, 1.01–1.02), ≥2 comorbidities (aOR, 2.9; 95% CI, 1.1–7.8), systemic corticosteroids (aOR, 6.9; 95% CI, 2.3–20.5), and sulfasalazine or 5-aminosalicylate use (aOR, 3.1; 95% CI, 1.3–7.7). Tumor necrosis factor antagonist treatment was not associated with severe COVID-19 (aOR, 0.9; 95% CI, 0.4–2.2). Conclusions Increasing age, comorbidities, and corticosteroids are associated with severe COVID-19 among patients with IBD, although a causal relationship cannot be definitively established. Notably, tumor necrosis factor antagonists do not appear to be associated with severe COVID-19.

The International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) is the only global organization devoted to the study of and management of the inflammatory bowel diseases (IBDs), namely, Crohn?s disease and ulcerative colitis. Membership is composed of physician-scientists who have established expertise in these diseases. The organization hosts an annual meeting and a number of working groups addressing issues of the epidemiology of IBD, diet and nutrition, and the development and use of treatments for IBD. There are currently 89 members of IOIBD representing 26 different countries. The organization has taken particular interest in the coronavirus disease-2019 (COVID-19) pandemic and how it may affect the IBD patient population. This document summarizes the results of 2 recent virtual meetings of the group and subsequent expert guidance for patients and providers.

Background & Aims Little is known about the effects of discontinuing mesalamine therapy for patients with Crohn’s disease (CD) who initiate therapy with an anti–tumor necrosis factor (anti-TNF) agent. We analyzed data from 2 national population cohorts to compare outcomes of patients with CD already on mesalamine therapy who started treatment with an anti-TNF agent and then either stopped or continued mesalamine. Methods The primary outcome was any adverse clinical event, defined as a composite of new corticosteroid use or CD-related hospitalization or surgery. We collected data from the Truven MarketScan (IBM, Armonk, NY) health claims database in the United States and the Danish health registers. Our analysis included patients with CD who started anti-TNF therapy after at least 90 days of oral mesalamine therapy. Patients were classified as stopping mesalamine if therapy was discontinued within 90 days of starting anti-TNF. We performed multivariable Cox regression models controlling for demographics, clinical factors, and health care utilization. Adjusted hazard ratios with 95% CIs were calculated, comparing stopping mesalamine with continuing mesalamine. Results A total of 3178 patients with CD were included in our final analysis (2960 in the United States and 218 in Denmark). Stopping mesalamine after initiating anti-TNF therapy was not associated with an increased risk of adverse clinical events in the US cohort (adjusted hazard ratio, 0.89; 95% CI, 0.77–1.03; P = .13) or in the Danish cohort (adjusted hazard ratio, 1.13; 95% CI, 0.68–1.87; P = .63). Similar results were obtained from sensitivity analyses of concomitant immunomodulator use and duration of mesalamine treatment before initiation of anti-TNF therapy. Conclusions In a retrospective analysis of 2 national databases, we found that stopping mesalamine therapy for patients with CD who were starting anti-TNF therapy did not increase their risk of adverse clinical events. These results should be validated in a prospective study.

Background Micronutrient deficiencies are common in patients with inflammatory bowel disease (IBD). To date, the majority of the literature has focused on vitamin D, vitamin B12, and iron deficiencies. We report a case series of patients with IBD and vitamin C deficiency. Methods We performed a retrospective chart review of 20 patients with IBD who had vitamin C deficiency (defined as a level ≤0.2 mg/dl) treated in a single tertiary care centre from February 2018 to October 2019. Demographics as well as disease characteristics and laboratory data were collected. In addition, data from routine nutritional assessments, performed by a nutritionist, were also included. Results Of these 20 patients, 11 (55%) were female with a median age of 27.5 years. Fifteen (75%) had Crohn’s disease (CD) and 5 (25%) had Ulcerative colitis (UC). Ten (50%) had been diagnosed with IBD within the last 3 years, and 10 (50%) had a duration of disease >5 years. Disease location was L1 ileal in 6 (30%) patients, L2 colonic in 5 (25%) and L3 ileocolonic in 9 (45%); behaviour was B1 non-stricturing, non-penetrating in 10 (50%) patients, B2 stricturing in 7 (35%) and B3 penetrating in 3 (15%). Nine (45%) patients had previous history of surgery. At the time of the study, 13 (87%, N=15) CD patients had a Harvey–Bradshaw Index >5, and 3 (60%, N = 5) UC patients had a Partial Mayo Score 5–7, indicating active disease. Overall, 14 (70%) patients were on biologic therapy. Sixteen (80%) patients had symptoms consistent with clinical scurvy, including 9 (45%) arthralgia, 6 (30%) dry brittle hair with hair loss, 4 (20%) pigmented rash, 3 (15%) gingivitis, 2 (10%) easy bruising and 1 (5%) brittle nails. Six (32%) had 3 or more of these clinical manifestations. Of those who underwent a nutrition evaluation (N = 18), 10 (56%) reported avoidance of all fruits and vegetables and 3 (17%) reported a reduction of fruits and vegetables in their diet. While all patients experienced vitamin C deficiency, some also had concomitant vitamin D, vitamin B12, iron and ferritin deficiencies (Table 1). Conclusion Vitamin C deficiency can occur in IBD patients and is associated with clinical symptoms of scurvy. Prospective studies are needed to evaluate prevalence of vitamin C deficiency in IBD and its ultimate impact on clinical outcomes. Meanwhile this study emphasises the need for appropriate dietary counselling in patients with IBD.

Background Incidentally diagnosed terminal ileitis has been reported among asymptomatic persons undergoing non-diagnostic colonoscopy. The purpose of our study was to determine the prevalence and long-term outcomes of asymptomatic terminal ileitis. Methods We developed and executed a systematic search strategy in three biomedical databases (Medline, Embase and Web of Science) and relevant scientific meeting abstracts, from inception to May 1, 2019, to identify observational studies that reported the prevalence of asymptomatic terminal ileitis in adults undergoing screening or polyp surveillance colonoscopy, and/or the long-term outcomes of such lesions. A random-effects meta-analysis was conducted to determine the pooled prevalence rate, confidence interval (CI), and report the heterogeneity score I2. Risk factors for progression to overt CD were abstracted. Results Of 2388 eligible studies, 1784 were screened after excluding duplicates, 84 were reviewed in full text and 14 studies were eligible for inclusion. Eight studies reported the prevalence of asymptomatic terminal ileitis in 46,460 persons undergoing non-diagnostic colonoscopy, and eight (two of eight reporting prevalence) studies reported follow-up data. The pooled rate of asymptomatic terminal ileitis was 1.5% (CI 1.0%, 16.3%), with I2 of 0 (Figure). The use of non-steroidal anti-inflammatory drugs varied between 0% and 37%. Of 147 persons with asymptomatic terminal ileitis with follow-up data (range 13–63.6 months in three studies), five had progression to CD, three were treated for CD with steroids, 5-amino salicylates, azathioprine and vedolizumab, and lesions resolved in four. Three studies reported the absence of symptoms as a predictor of lack of progression. Conclusion Asymptomatic terminal ileitis can be found incidentally in 1.5% of non-diagnostic colonoscopies. Based on limited data, the rate of its progression to overt CD seems low, and watchful waiting could likely be a reasonable strategy. More long-term follow-up studies are needed to inform the natural history of incidental terminal ileitis, factors that predict progression to CD and therapeutic implications.

ObjectiveThe benefit of continuing 5-aminosalicylate (5-ASA) in patients with ulcerative colitis (UC) who initiate anti-tumour necrosis factor-alpha (anti-TNF) biologics is unknown. We aimed to compare clinical outcomes in patients with UC already on 5-ASA who started anti-TNF and then either stopped or continued 5-ASA.DesignOur primary outcome was any adverse clinical event defined as a composite of new corticosteroid use, UC-related hospitalisation or surgery. We used two national databases: the United States (US) Truven MarketScan health claims database and the Danish health registers. Patients with UC who started anti-TNF after having been on oral 5-ASA for at least 90 days were included. Patients were classified as stopping 5-ASA if therapy was discontinued within 90 days of starting anti-TNF. We performed multivariable Cox regression models controlling for demographics, clinical factors and healthcare utilisation. Adjusted HRs (aHR) with 95% CI are reported comparing stopping 5-ASA with continuing 5-ASA.ResultsA total of 3589 patients with UC were included (2890 US and 699 Denmark). Stopping 5-ASA after initiating anti-TNF was not associated with an increased risk of adverse clinical events in the U.S. cohort (aHR 1.04; 95% CI 0.90 to 1.21, p=0.57) nor in the Danish cohort (aHR 1.09; 95% CI 0.80 to 1.49, p=0.60). Results were similar in sensitivity analyses investigating concomitant immunomodulator use and duration of 5-ASA treatment before initiating anti-TNF.ConclusionIn two national databases, stopping 5-ASA in patients with UC starting anti-TNF therapy did not increase the risk of adverse clinical events. These results should be validated in a prospective clinical trial.

The goals for treatment of inflammatory bowel diseases (IBDs) are changing from elimination of symptoms toward complete disease control—a process that demands both clinical and endoscopic remission. This new IBD treatment paradigm has been shifting from a conventional “step-up” approach toward a more “top-down” early intervention treatment strategy. Recent studies suggest that the use of biologic agents, specifically those targeting tumor necrosis factor alpha, earlier in the treatment course improves patient outcomes and can prevent progression to irreversible bowel damage. Although the strategy of early intervention has accumulating evidence in Crohn’s disease, there is less evidence supporting its impact in ulcerative colitis.

Crohn’s disease (CD) follows a relapsing and remitting course incurring cumulative bowel damage over time. The question of whether or not the timing of the initiating biologic therapy affects long-term disease progression remains unanswered. Herein, we calculated rates of change in the Lemann index—which quantifies accumulated bowel damage—as a function of the time between the disease onset and initiation of biologic therapy. We aimed to explore the impact of the earlier introduction of biologics on the rate of progression of long-term cumulative bowel damage. Medical records of CD patients treated during 2009–2014 at The Mount Sinai Hospital were queried. Inclusion criteria were two comprehensive assessments allowing calculation of the index at t1 and t2: two time-points ≥ 1 year apart. Patients with biologics introduced before or within 3 months at inclusion (t1) were defined as Bio-pre-t1 and those who did not as Bio-post-t1. The rate of disease progression was calculated as the change in the index per year during t1–t2. A total of 88 patients were studied: 58 Bio-pre-t1 and 30 Bio-post-t1. Among the 58 Bio-pre-t1 cases, damage progressed in 29 (50%), regressed in 20 (34.5%), and stabilized in 9 (15.5%). Median time to initiation of biologics among patients whose index improved was nominally shorter compared to that in patients whose index progressed (8 vs. 15 years). Earlier introduction of biologics tended to correlate with the slower rate of progression (ρ = 0.241; p = 0.069). Earlier introduction of biologics tended to correlate with the slower progression of bowel damage in CD, reflected by the reduced rate of Lemann index progression.

Perianal fistulizing disease is an aggressive and debilitating phenotype of Crohn's disease (CD), representing a significant therapeutic challenge. New work has led to advancement in epidemiology and long-term outcomes of perianal disease. The range of therapeutic options continues to expand, including new biologic agents, biosimilars, and stem cell therapy. Areas covered: We discuss updates to all aspects of management of perianal disease, with a focus on the last 3 years of published data. Areas considered include new data on epidemiology and prognostication, medical and surgical therapy, and stem cell therapy. Expert commentary: The presence of perianal disease at CD diagnosis portends a significantly worse disease course. Patients with perianal disease require close monitoring to identify those who are at risk for worsening disease, suboptimal biologic drug levels, and signs of developing neoplasm. With the impending availability of local mesenchymal stem cell therapy, this becomes increasingly important as this therapy, although extremely promising, is thus far only effective in patients without proctitis.

To identify factors that regulate gut microbiota density and the impact of varied microbiota density on health, we assayed this fundamental ecosystem property in fecal samples across mammals, human disease, and therapeutic interventions. Physiologic features of the host (carrying capacity) and the fitness of the gut microbiota shape microbiota density. Therapeutic manipulation of microbiota density in mice altered host metabolic and immune homeostasis. In humans, gut microbiota density was reduced in Crohn’s disease, ulcerative colitis, and ileal pouch-anal anastomosis. The gut microbiota in recurrent Clostridium difficile infection had lower density and reduced fitness that were restored by fecal microbiota transplantation. Understanding the interplay between microbiota and disease in terms of microbiota density, host carrying capacity, and microbiota fitness provide new insights into microbiome structure and microbiome targeted therapeutics.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

Patients with inflammatory bowel disease (IBD) involving the colon are at increased risk of developing colorectal cancer. Surveillance colonoscopy to detect dysplasia and early colorectal cancer is therefore one of the key elements of health care maintenance in IBD patients. In general, patients with left-sided or extensive colitis should have surveillance exams every 1–2 years starting 8 years after diagnosis. Dysplasia surveillance has typically involved taking four-quadrant random biopsies throughout the colon. However, numerous studies have demonstrated that targeted examination using chromoendoscopy (CE) increases the detection of dysplastic lesions compared to standard-definition white-light colonoscopy and is recommended by the SCENIC international consensus statement. CE is an enhanced visualization technique that involves spraying the colon with a contrast dye, typically methylene blue or indigo carmine. It remains to be definitively determined if CE is better than high-definition white-light colonoscopy and if removing lesions detected by CE leads to meaningful changes in long-term management and colorectal cancer risk.

The original version of the article unfortunately contained a couple of errors. In 'methods' section, in 'Outcomes' subsection, the sentence 'Endoscopic remission was defined as an SESCD ≤ 2 in patients with CD and an EMS ≤ 2 in UC patients while off corticosteroids.'

Background Vedolizumab is a gut-selective antibody to α4 β7 integrin approved to treat moderate-to-severe Crohn's disease and ulcerative colitis in adults. Inflammatory bowel disease (IBD) and immunosuppressant use are associated with increased risk of malignancy. Aim To analyse the incidence of malignancy with vedolizumab treatment in the GEMINI long-term safety (LTS) study and post-marketing (PM) setting. Methods Malignancy data from the LTS study (May 2009 to May 2018), and data from the vedolizumab Global Safety Database (20 May 2014 to 19 May 2018), were identified using Medical Dictionary for Regulatory Activities coding. The number of patients experiencing malignancies in the LTS study (excluding malignancies within 1 year following vedolizumab initiation) was indirectly standardised against the number expected, using age- and sex-specific rates in patients with IBD from Optum's Clinformatics™ Data Mart (CDM) database. Results Among 1785 patients with ≥1 year of follow-up post-vedolizumab initiation in the LTS study (total 5670 patient-years), observed numbers of malignancies were similar to those expected compared with CDM data (31 vs 29; ratio of observed to expected events = 1.08; P = 0.71; 95% confidence intervals [CI] 0.73, 1.53). The most common malignancies were renal and bladder (6). PM, 293 patients reported 299 malignancies (including malignancies within 1 year following vedolizumab initiation), in approximately 208 050 patient-years of vedolizumab exposure. Lower gastrointestinal malignancies were most common (59). Conclusions The number of malignancies in the LTS study was similar to that expected from an IBD population with no statistically significant differences, although few confounders could be corrected for. Limitations of PM safety reporting require consideration; however, the number of malignancies with vedolizumab appeared low.