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Objective Gut fibrosis occurs under chronic inflammation. This study examined the effects of different cyclooxygenase (COX) inhibitors on fibrosis in the inflamed colon. Methods Colitis was induced by 2,4-dinitrobenzenesulfonic acid (DNBS) in albino male Sprague–Dawley rats. After 6, 12 and 18 days, macroscopic and microscopic damage, collagen and elastic fibre content were examined. At day 6, pro-fibrotic factors (collagen I and III, hydroxyproline, fibronectin, matrix metalloproteinase-2 and -9), transforming growth factor-beta (TGF-β) signalling [TGF-β, Ras homolog gene family member A (RhoA), phosphorylated small mother against decapentaplegic (pSMAD)-2 and -6] and peristalsis were assessed, and the effects of indomethacin, SC-560 or celecoxib were tested. Key findings Six days after DNBS administration, significant histopathological signs of fibrotic remodelling were observed in rats. At day 6, pro-fibrotic factors were up-regulated and colonic peristalsis was altered. COX inhibitors reversed the histochemical, molecular and functional changes in the fibrotic colon. COX inhibition reduced TGF-β expression, SMAD2 phosphorylation and RhoA, and increased SMAD6 expression. Conclusions Colonic fibrosis is associated with altered bowel motility and induction of profibrotic factors driven by TGF-β signalling. COX-1 and COX-2 inhibition counteracts this fibrotic remodelling by the modulation of TGF-β/SMAD signalling, mainly via SMAD6 induction and reduction in SMAD2 phosphorylation.

Background and Aims Patients with longstanding inflammatory bowel disease [IBD] may be at an increased risk of death compared to the general population, especially elderly patients. The Inflammatory Bowel South-Eastern Norway [IBSEN] study has previously detected a small but not statistically significant increase in mortality 20 years after diagnosis. The aim of this study was to evaluate the overall and cause-specific mortality at 30 years of follow-up. Methods The IBSEN cohort included 519 incident patients with ulcerative colitis [UC] and 237 patients with Crohn’s disease [CD] between 1990 and 1993, each matched with five controls. Death certificate data were obtained from the Norwegian Cause of Death Registry. The underlying causes of death were categorized into five groups: all cancers, gastrointestinal cancers, cardiovascular diseases, infections and all other causes. Hazard ratios [HRs] were modelled using Cox regression. Results There was no statistically significant difference in the overall mortality rates. However, in patients with CD, male sex (HR = 1.65 [95% CI: 1.04–2.62]), onset after 40 years of age (HR = 1.72 [1.19–2.48]), colonic disease (HR = 1.57 [1.05–2.35]) and penetrating behaviour (HR = 3.3 [1.41–7.76]) were clinical factors associated with an increased mortality. IBD patients were at a higher risk of death due to cardiovascular disease: HR = 1.51 [1.10–2.08] for UC and 2.04 [1.11–3.77] for CD. When taking into account both the underlying and the immediate cause of death, infection was more frequent in patients with IBD. Conclusions Overall, all-cause mortality rates were similar between patients with IBD and controls. However, clinicians should remain alert to cardiovascular diseases and infections, particularly in specific subgroups of CD patients.

Background and aim: Pneumocystis jirovecii pneumonia [PJP] is a very rare, potentially life-threatening pulmonary fungal infection that occurs in immunocompromised individuals including patients with inflammatory bowel disease [IBD]. Our aim was to describe immunosuppressive treatment exposure as well as the outcome in IBD patients with PJP.Methods: PJP cases were retrospectively collected through the COllaborative Network For Exceptionally Rare case reports of the European Crohn's and Colitis Organisation. Clinical data were provided through a case report form.Results: In all, 18 PJP episodes were reported in 17 IBD patients [10 ulcerative colitis and seven Crohn's disease]. The median age at PJP diagnosis was 55 years (interquartile range [IQR], 40-68 years]. Two PJP [11.1%] occurred in patients on triple immunosuppression, 10 patients [55.6%] had double immunosuppressive treatment, four patients [22.2%] had monotherapy and two PJP occurred in absence of immunosuppressive treatment [one in a human immunodeficiency virus patient and one in a patient with a history of autologous stem cell transplantation]. Immunosuppressive therapies included steroids [n = 12], thiopurines [n = 10], infliximab [n = 4], ciclosporin [n = 2], methotrexate [n = 1], and tacrolimus [n = 1]. None of the patients diagnosed with PJP had received prophylaxis. All patients were treated by trimethoprim/sulphamethoxazole or atovaquone and an intensive care unit [ICU] stay was required in seven cases. Two patients [aged 71 and 32 years] died, and one patient had a recurrent episode 16 months after initial treatment. Evolution was favourable for the others.Conclusion: This case series reporting potentially fatal PJP highlights the need for adjusted prophylactic therapy in patients with IBD on immunosuppressive therapy. Background and aim: Pneumocystis jirovecii pneumonia [PJP] is a very rare, potentially life-threatening pulmonary fungal infection that occurs in immunocompromised individuals including patients with inflammatory bowel disease [IBD]. Our aim was to describe immunosuppressive treatment exposure as well as the outcome in IBD patients with PJP.Methods: PJP cases were retrospectively collected through the COllaborative Network For Exceptionally Rare case reports of the European Crohn's and Colitis Organisation. Clinical data were provided through a case report form.Results: In all, 18 PJP episodes were reported in 17 IBD patients [10 ulcerative colitis and seven Crohn's disease]. The median age at PJP diagnosis was 55 years (interquartile range [IQR], 40-68 years]. Two PJP [11.1%] occurred in patients on triple immunosuppression, 10 patients [55.6%] had double immunosuppressive treatment, four patients [22.2%] had monotherapy and two PJP occurred in absence of immunosuppressive treatment [one in a human immunodeficiency virus patient and one in a patient with a history of autologous stem cell transplantation]. Immunosuppressive therapies included steroids [n = 12], thiopurines [n = 10], infliximab [n = 4], ciclosporin [n = 2], methotrexate [n = 1], and tacrolimus [n = 1]. None of the patients diagnosed with PJP had received prophylaxis. All patients were treated by trimethoprim/sulphamethoxazole or atovaquone and an intensive care unit [ICU] stay was required in seven cases. Two patients [aged 71 and 32 years] died, and one patient had a recurrent episode 16 months after initial treatment. Evolution was favourable for the others.Conclusion: This case series reporting potentially fatal PJP highlights the need for adjusted prophylactic therapy in patients with IBD on immunosuppressive therapy.

Background Serious infections have been observed in patients with inflammatory bowel disease (IBD) on anti-TNF use—but to what extent these infections are due to anti-TNF or the disease activity per se is hard to disentangle. We aimed to describe how the rates of serious infections change over time both before and after starting anti-TNF in IBD. Methods Inflammatory bowel disease patients naïve to anti-TNF treatment were identified at 5 centers participating in the Swedish IBD Quality Register, and their medical records examined in detail. Serious infections, defined as infections requiring in-patient care, the year before and after the start of anti-TNF treatment were evaluated. Results Among 980 patients who started their first anti-TNF therapy between 1999 and 2016, the incidence rate of serious infections was 2.19 (95% CI,1.43-3.36) per 100 person years the year before and 2.11 (95% CI, 1.33-3.34) per 100 person years 1 year after treatment start. This corresponded to an incidence rate ratio 1 year after anti-TNF treatment of 0.97 (95% CI, 0.51-1.84). Compared with before anti-TNF therapy, the incidence of serious infection was significantly decreased more than 1 year after treatment (incidence rate ratio 0.56; 95% CI, 0.33-0.95; P = .03). Conclusions In routine clinical practice in Sweden, the incidence rate of serious infection among IBD patients did not increase with anti-TNF therapy. Instead, serious infections seemed to decrease more than 1 year after initiation of anti-TNF treatment.

Background To assess treatment response, objective measures are superior to clinical improvement in Crohn’s disease [CD]. Intestinal ultrasound [IUS] is an attractive, non-invasive alternative to endoscopy, demonstrating early transmural changes after treatment initiation. Therefore, we investigated IUS and contrast-enhanced ultrasound [CEUS] to predict [early] endoscopic treatment response. Methods Consecutive patients with endoscopically active CD, starting anti-TNFα therapy, were included. Clinical, biochemical, IUS, and CEUS parameters at baseline [T0], after 4–8 weeks [T1] and 12–34 weeks [T2] were collected. The most severely inflamed segment at endoscopy (highest segmental Simplified Endoscopic Score for Crohn’s Disease [SES-CD]) and IUS (highest segmental bowel wall thickness [BWT]) was identified. At T2, endoscopic response [decrease in SES-CD ≥ 50%] and remission [SES-CD = 0] were scored. Results A total of 40 patients were included: 14 reached endoscopic remission and 17 endoscopic response. At T1 (3.1 mm [1.9–4.2] vs 5.3 mm [3.8–6.9], p = 0.005) and T2 (2.0 mm [1.8–3.1] vs 5.1 [3.0–6.3] mm, p = 0.002) BWT was lower in patients with endoscopic remission. At T1 and T2, 18% (area under the receiver operating curve [AUROC]: 0.77; odds ratio [OR]: 10.80, p = 0.012) and 29% [AUROC: 0.833; OR: 37.50, p = 0.006] BWT decrease predicted endoscopic response, respectively. To determine endoscopic remission, BWT 3.2 mm was most accurate [AUROC: 0.94; OR: 39.42, p < 0.0001] at T2. In addition, absence of colour Doppler signal [OR: 13.76, p = 0.03] and the CEUS parameter wash-out rate [OR: 0.76, p = 0.019] improved the prediction model. Conclusions Reduction in BWT, already after 4–8 weeks of follow-up, predicted endoscopic response and remission. CEUS parameters were of limited value. Furthermore, we have provided accurate cut-offs for BWT reflecting endoscopic response and remission at different time points.

Background and Aims Inflammatory Bowel Disease colitis-associated dysplasia is managed with either enhanced surveillance and endoscopic resection or prophylactic surgery. The rate of progression to cancer after a dysplasia diagnosis remains uncertain in many cases and patients have high thresholds for accepting proctocolectomy. Individualised discussion of management options is encouraged to take place between patients and their multidisciplinary teams for best outcomes. We aimed to develop a toolkit to support a structured, multidisciplinary and shared decision-making approach to discussions about dysplasia management options between clinicians and their patients. Methods Evidence from systematic literature reviews, mixed-methods studies conducted with key stakeholders and decision-making expert recommendations were consolidated to draft consensus statements by the DECIDE steering group. These were then subjected to an international, multidisciplinary modified electronic Delphi process until an a priori threshold of 80% agreement was achieved to establish consensus for each statement. Results 31 members (15 gastroenterologists, 14 colorectal surgeons and two nurse specialists) from 9 countries formed the Delphi panel. We present the 18 consensus statements generated after two iterative rounds of anonymous voting. Conclusions By consolidating evidence for best practice using literature review, key stakeholder and decision-making expert consultation we have developed international consensus recommendations to support healthcare professionals counselling patients on the management of high cancer risk colitis-associated dysplasia. The final toolkit includes clinician and patient decision aids to facilitate shared decision-making.

MicroRNAs [miRNAs], small non-coding RNAs, have recently been described as crucial contributors to intestinal homeostasis. They can interact with the gut microbiota in a reciprocal manner and deeply affect host health status, leading to several disorders when unbalanced. Inflammatory bowel disease [IBD] is a chronic inflammation of the gastrointestinal tract that co-occurs with alterations of the gut microbiota, and whose aetiology remains largely unclear. On one hand, host miRNA could be playing a relevant role in IBD pathophysiology by shaping the gut microbiota. The gut microbiome, on the other hand, may regulate the expression of host miRNAs, resulting in intestinal epithelial dysfunction, altered autophagy, and immune hyperactivation. Interestingly, it has been hypothesised that their reciprocal impact may be used for therapeutic goals. This review describes the latest research and suggests mechanisms through which miRNA and intestinal microbiota, as joint actors, may participate specifically in IBD pathophysiology. Furthermore, we discuss the diagnostic power and therapeutic potential resulting from their bidirectional communication after faecal transplantation, probiotics intake, or anti-miRNAs or miRNA mimics administration. The current literature is summarised in the present work in a comprehensive manner, hoping to provide a better understanding of the miRNA-microbiota cross-talk and to facilitate their application in IBD.

Background Patients with inflammatory bowel disease (IBD) on immune-modifying treatment could be at an increased risk for severe coronavirus disease 2019 (COVID-19); thus, data on the efficacy and safety of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines are essential. We conducted a prospective study of IBD patients vaccinated with BNT162b2, CX-024414, and ChAdOx1 nCoV-19 vaccines. The aim was to evaluate the rate and magnitude of seroconversion, assess the effect of different immune-modifying treatment modalities on the magnitude of anti-SARS-CoV-2 IgG antibody levels, and analyze the impact of anti-SARS-CoV-2 vaccination on the inflammatory biomarkers of IBD. Methods The study included 602 IBD patients and 168 immunocompetent health care workers serving as controls. Serum anti-SARS-CoV-2 IgG antibodies were measured by chemiluminescent microparticle immunoassay before the vaccination and 8 weeks after the vaccination. Results Of IBD patients, 82.2% were receiving biological treatment: most of them were treated with antitumor necrosis factor (TNF)-α inhibitors (48.5%), and just under half of them were treated with concomitant thiopurines or methotrexate, followed by vedolizumab (18.6%) and ustekinumab (15.1%). Only 8.1% of patients were on 5-aminosalicylates, and a minority (2.2%) were treatment-free. The postvaccine seropositivity rate among IBD patients and controls was 97.8% vs 100%. Median anti-SARS-CoV-2 IgG levels were lower among IBD recipients of ChAdOx1 nCoV-19 compared with 2 other vaccines (P < .0001) and control ChAdOx1 nCoV-19 recipients (P = .01). No correlation was found between serum trough levels and anti-SARS-CoV-2 IgG concentrations for any of the biological drugs used. The TNF-α inhibitors with concomitant immunosuppressive treatment but no other treatment modalities were associated with a lower postvaccination antibody response (P < .0001). When evaluating the laboratory activity of IBD by C-reactive protein and fecal calprotectin levels, no significant differences were found before the vaccination and 8 weeks after its completion. Conclusions Our findings warrant particular attention to the anti-SARS-CoV-2 vaccination of IBD patients treated with TNF-α inhibitors with concomitant immunomodulators and show the priority of mRNA vaccines in this specific group of patients.

Background Etrolizumab, a humanized anti-β7 antibody, has not been studied in children. Here, we evaluate the pharmacokinetics, pharmacodynamics, and safety of etrolizumab in children with inflammatory bowel disease. Methods Patients age 4 to 17 years with moderately to severely active ulcerative colitis or Crohn’s disease were randomized 1:1 to receive 1.5mg/kg of etrolizumab subcutaneously every 4 weeks (q4w) or 3.0mg/kg every 8 weeks (q8w) for 16 weeks in this open-label phase 1 trial. Pharmacokinetics, pharmacodynamics, safety, and efficacy were assessed. Results Of the 24 patients treated, 21 completed the study. In the groups of 1.5mg/kg q4w and 3.0mg/kg q8w, respectively, mean (SD) maximum concentration (Cmax) was 9.8 (4.86) µg/mL and 18.1 (6.25) µg/mL; and mean (SD) area under the curve within a dosing interval (AUCtau) was 167 (86.9) and 521 (306) μg·day/mL after the last dose. The Cmax increased dose proportionally. The AUC over an 8-week period was slightly higher in the 3.0mg/kg q8w dose group. Median half-life was similar for both dosing regimens. Median numbers of free β7high gut-homing T and B cell subsets declined below 10% of baseline, confirming β7 target engagement and complete/near-complete receptor occupancy. Adverse events were consistent with the safety profile in adults. Approximately 60% of patients achieved a clinical response. Conclusions Etrolizumab showed a dose-proportional increase in Cmax and a slightly greater than dose-proportional increase in AUCtau. Both regimens achieved complete/near-complete β7 receptor occupancy, with a similar relationship to concentration as adults. Etrolizumab was well tolerated and demonstrated clinical activity in children.

Background and Aims Filgotinib is a small molecule that selectively inhibits Janus kinase [JAK] type 1. It is already approved for the treatment of rheumatoid arthritis and is being evaluated for the management of patients with moderate to severe ulcerative colitis [UC]. The purpose of this review is to provide an overview of the currently available data on filgotinib and to define how to position this new drug in the treatment algorithm of patients with UC. Methods The Pubmed, Embase and Scopus databases were searched up to June 25, 2021 in order to identify studies reporting efficacy and safety data of filgotinib in patients with UC. Results Data from a phase III study enrolling UC patients with moderate to severe disease show that filgotinib is effective with a reassuring safety profile. Filgotinib treatment is not associated with a greater risk of thrombosis and herpes zoster infections compared to other JAK inhibitors. However, animal studies reported impaired spermatogenesis and histopathological effects on male reproductive organs, making it necessary to deepen this aspect in dedicated human studies. Conclusions Filgotinib is an effective and safe drug for treatment of both biologic-naive and biologic-experienced patients with moderate to severe UC and may soon be available.

Despite recent developments in therapy for inflammatory bowel diseases (IBDs), there have been limited advances in diagnostic tools available to aid in disease management. A growing body of evidence suggests that there are important host-microbe interactions at the mucosal interface that modulate the inflammatory response in patients with IBD. Additionally, the importance of mucosal integrity and its disruption appears to be important in the pathophysiology and perpetuation of the disease. The ability to characterize this interface may provide valuable information for both disease monitoring and identification of new treatment targets. Endoscopy remains the primary tool for disease monitoring, and mucosal healing is the primary therapeutic target in IBD treatment. However, establishing mucosal healing requires repetitive endoscopic procedures, and endoscopy is limited by factors such as invasiveness, cost, and risk of adverse events. Moreover, the use of a bowel preparation for colonoscopies alters the mucus layer and thus perturbs evaluation of the host-microbe interaction. Stool sampling may also be inaccurate because it reflects the end state of metabolites and proteins, failing to take into account the degradation or alteration of substrates of interest by bacterial proteases and other enzymes during passage through the colon. A novel sampling capsule, called the Recoverable Sampling System (RSS), is being developed as a complementary tool to colonoscopy. The RSS is intended to be a platform for noninvasive autonomous sampling, preservation, handling, and storage of analytes of interest found in the gastrointestinal fluids. A proprietary preservative contained within the chambers of the capsule has been developed to stabilize DNA and proteins for ex vivo microbiome and metabolomics analyses. Surrogate markers such as SPP24 and GUCA2a have been identified to correlate with gut health, intestinal permeability, and inflammation and could be locally sampled by the RSS. The potential clinical utility of an RSS device is broad and would likely be able to guide therapy by allowing for more frequent disease monitoring, aiding in disease characterization, and facilitating in the identification of novel therapeutic targets.A new technology is being developed, Recoverable Sampling System (RSS), that may allow sampling without a colonoscopy. This may lead to new biomarkers and even drug targets which may ultimately improve the care of these patients.

Background Children with inflammatory bowel disease [IBD] are disproportionally affected by recurrent Clostridioides difficile infection [rCDI]. Although faecal microbiota transplantation [FMT] has been used with good efficacy in adults with IBD, little is known about outcomes associated with FMT in paediatric IBD. Methods We performed a retrospective review of FMT at 20 paediatric centres in the USA from March 2012 to March 2020. Children with and without IBD were compared with determined differences in the efficacy of FMT for rCDI. In addition, children with IBD with and without a successful outcome were compared with determined predictors of success. Safety data and IBD-specific outcomes were obtained. Results A total of 396 paediatric patients, including 148 with IBD, were included. Children with IBD were no less likely to have a successful first FMT then the non-IBD affected cohort [76% vs 81%, p = 0.17]. Among children with IBD, patients were more likely to have a successful FMT if they received FMT with fresh stool [p = 0.03], were without diarrhoea prior to FMT [p = 0.03], or had a shorter time from rCDI diagnosis until FMT [p = 0.04]. Children with a failed FMT were more likely to have clinically active IBD post-FMT [p = 0.002] and 19 [13%] patients had an IBD-related hospitalisation in the 3-month follow-up. Conclusions Based on the findings from this large US multicentre cohort, the efficacy of FMT for the treatment of rCDI did not differ in children with IBD. Failed FMT among children with IBD was possibly related to the presence of clinically active IBD.

The risk of hospitalization and death from Coronavirus disease-19 (COVID-19) increases with age. The extreme elderly have been particularly vulnerable, with those above the age of 80 having a case-fatality rate as high as 15%. Aging of the immune system can lead to impaired inflammatory responses where eradication of an organism such as Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV2) is inadequate but is exaggerated in such a way as to enhance pneumonia and acute respiratory distress syndrome. Frailty and comorbidity are both more common in the elderly, and these can enhance the morbidity and mortality from COVID-19. Studies from Northern California and Italy suggest that elderly persons with inflammatory bowel disease (IBD) were more likely to acquire SARS-CoV-2 infection than youths with IBD. While the specific impact of age-related comorbidity is less well established among people with IBD who acquire COVID-19, data from the Surveillance Epidemiology of Coronavirus Under Research Exclusion (SECURE-IBD) database reported that having two or more chronic illnesses was independently associated with developing severe COVID-19 among people with IBD. Despite having exaggerated auto-inflammatory responses, people with IBD do not appear to have an overall increased risk of developing severe COVID-19 than the general population. However, whether seniors with IBD do worse once they acquire COVID-19 compared with seniors without IBD is not known. The advent of telehealth care has posed an information technology challenge for many seniors with and without IBD. Most persons with IBD have expressed satisfaction with virtual IBD health care (phone or video-based visits). While the elderly may have less robust immune responses to vaccinations, learning from experiences with other vaccination programs, especially influenza, have shown that vaccinating seniors decreases both morbidity and mortality and, in turn, healthcare resources.

The prevalence of inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis, in Canada, is over 0.75% in 2021. Many individuals with IBD are immunocompromised. Consequently, the World Health Organization’s declaration of a global pandemic uniquely impacted those with IBD. Crohn’s and Colitis Canada (CCC) formed the COVID-19 and IBD Taskforce to provide evidence-based guidance during the pandemic to individuals with IBD and their families. The Taskforce met regularly through the course of the pandemic, synthesizing available information on the impact of COVID-19 on IBD. At first, the information was extrapolated from expert consensus guidelines, but eventually, recommendations were adapted for an international registry of worldwide cases of COVID-19 in people with IBD. The task force launched a knowledge translation initiative consisting of a webinar series and online resources to communicate information directly to the IBD community. Taskforce recommendations were posted to CCC’s website and included guidance such as risk stratification, management of immunosuppressant medications, physical distancing, and mental health. A weekly webinar series communicated critical information directly to the IBD community. During the pandemic, traffic to CCC’s website increased with 484,755 unique views of the COVID-19 webpages and 126,187 views of the 23 webinars, including their video clips. CCC’s COVID-19 and IBD Taskforce provided critical guidance to the IBD community as the pandemic emerged, the nation underwent a lockdown, the economy reopened, and the second wave ensued. By integrating public health guidance through the unique prism of a vulnerable population, CCC’s knowledge translation platform informed and protected the IBD community.

Inflammatory bowel disease (IBD) is a disease that results from dysregulation of the immune system and frequently requires medications that can affect the immune response to infections; therefore, it was imperative to quickly understand the risk of coronavirus disease 2019 (COVID-19) infection on persons living with IBD and how that risk may be increased by commonly used IBD medications. The IBD research community in Canada and beyond quickly established collaborative efforts to better understand the specific risk posed by COVID-19 on persons with IBD. We learned that IBD itself was not a risk factor for death or serious complications of COVID-19, and that most commonly used drug classes (with the notable exception of corticosteroids) do not increase the risk of COVID-19-related adverse outcomes. The risk factors for serious complications and death from COVID-19 appear to be similar to those identified in the wider population; those being advanced age, having pre-existing heart or lung disease, and smoking. We recommend that persons with IBD do not alter their course of therapy to avoid complications of COVID-19, though the indiscriminate use of corticosteroids should be avoided. Persons with IBD should follow the same public health recommendations as the general population to reduce their personal risk of acquiring COVID-19.

At the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there were many unknowns: transmission vectors of the virus, appropriate intervention strategies and if being immunocompromised due to inflammatory bowel disease (IBD), for example, or medications put a person at increased risk for severe COVID-19. Imposing and relaxing of public health restrictions at different times and in different regions in Canada led to different epidemiologies of the virus in different provinces and territories. In order to understand the waxing and waning of waves of the COVID-19 pandemic, it is necessary to understand the effective reproductive number (Rt) and the countervailing forces that exert upward or downward pressure on the spread of the virus at a given point in time. As many regions in Canada deal with a third wave, the primary forces affecting the Rt of severe acute respiratory syndrome coronavirus 2 are variants of concern and the increasing vaccinations of Canadians leading to increased population-level immunity. Fortunately, for the IBD population, current research suggests that those with IBD are not at increased risk of contracting COVID-19, nor of having a more severe disease course when compared to the general population.

Background Ulcerative colitis (UC) and Crohn’s disease (CD) are 2 subtypes of inflammatory bowel disease (IBD). Several studies have reported brain abnormalities in IBD patients. This study aims to identify differences of gray matter volume (GMV) between patients with UC and healthy controls (HCs). Methods Fifty-seven patients with UC and 40 HCs underwent structural magnetic resonance imaging. Voxel-based morphometry method was used to detect GMV differences. Receiver operating characteristic (ROC) curve was applied to investigate reliable biomarkers for identifying patients with UC from HCs. Regression analysis was used to examine relationships between the structure alternations and clinical symptoms. Results Compared with HCs, patients with UC showed decreased GMV in the insula, thalamus, pregenual anterior cingulate cortex, hippocampus/parahippocampus, amygdala, and temporal pole; they showed increased GMV in the putamen, supplementary motor area, periaqueductal gray, hypothalamus, and precentral gyrus. Receiver operating characteristic analysis showed the highest classification power of thalamus. The inclusion of anxiety and depression as covariates eliminated the differences in the right insula, pregenual anterior cingulate cortex, supplementary motor area, and precentral gyrus. Most of the GMV changes were found in active patients with UC, with few changes in patients with UC in remission. We also found significantly negative correlation between UC duration and GMV in several regions. Conclusion The current neuroimaging findings were involved in visceral sensory pathways and were partially associated with the levels of anxiety and depression and clinical stage of patients with UC. This study might provide evidence for possible neuromechanisms of UC.

Objectives To describe new-onset IBD (new IBD) in patients treated with IL-17 inhibitors (IL-17i), to assess their incidence and to identify their risk factors in real life. Methods A French national registry (MISSIL) aimed to report all cases of new IBD in patients treated with IL-17i from January 2016 to December 2019. Using the estimated number of patients treated by IL-17 in France during the study period, the annual incidence rates of new IBD was reported in IL-17i-treated patients. A case–control study was performed with two controls per new IBD case matched by gender, age and underlying inflammatory disease. Results Thirty-one cases of new IBD under IL-17i were collected: 27 patients treated for spondyloarthritis and four patients for psoriasis. All were observed with secukinumab (SEK). The median time to onset of new IBD symptoms was 4.0 (1.5–7.5) months. SEK was discontinued in all patients. The evolution was favourable with complete resolution (17/31), improvement (7/31) or stabilization (5/31). Two patients died: one due to a massive myocardial infarction and one due to post-colectomy complications. The incidence of new IBD decreased from 0.69/100 patient-years [PY] (7/1010) in 2016 to 0.08/100 PY (6/7951) in 2019. No previous treatment with etanercept (odds ratio [OR] = 0.33, 95% CI: 0.14–0.80, P = 0.014) and low number of previous biologic therapies (OR = 0.67, 95% CI: 0.47, 0.94, P = 0.021) were significantly associated with new IBD. Conclusion The incidence of new IBD was low and decreased from 2016 to 2019. The outcome was favourable in 24 out of 31 patients, but two patients died.

Background Intestinal neutrophil recruitment is a characteristic feature of the earliest stages of inflammatory bowel disease (IBD). Neutrophil elastase (NE) and myeloperoxidase (MPO) mediate the formation of neutrophil extracellular traps (NETs); NETs produce the bactericidal oxidant hypochlorous acid (HOCl), causing host tissue damage when unregulated. The project aim was to investigate the relationship between NET formation and clinical IBD in humans. Methods Human intestinal biopsies were collected from Crohn’s disease (CD) patients, endoscopically categorized as unaffected, transitional, or diseased, and assigned a histopathological score. Results A significant linear correlation was identified between pathological score and cell viability (TUNEL+). Immunohistochemical analysis revealed the presence of NET markers NE, MPO, and citrullinated histone (CitH3) that increased significantly with increasing histopathological score. Diseased specimens showed greater MPO+-immunostaining than control (P < .0001) and unaffected CD (P < .0001), with transitional CD specimens also showing greater staining than controls (P < .05) and unaffected CD (P < .05). Similarly, NE+-immunostaining was elevated significantly in diseased CD than controls (P < .0001) and unaffected CD (P < .0001) and was significantly higher in transitional CD than in controls (P < .0001) and unaffected CD (P < .0001). The CitH3+-immunostaining of diseased CD was significantly higher than controls (P < .05), unaffected CD (P < .0001) and transitional CD (P < .05), with transitional CD specimens showing greater staining than unaffected CD (P < .01). Multiplex immunohistochemistry with z-stacking revealed colocalization of NE, MPO, CitH3, and DAPI (cell nuclei), confirming the NET assignment. Conclusion These data indicate an association between increased NET formation and CD severity, potentially due to excessive MPO-mediated HOCl production in the extracellular domain, causing host tissue damage that exacerbates CD.

Background The prevalence of obesity and the number of bariatric surgeries in both the general population and in patients with inflammatory bowel disease (IBD) have increased significantly in recent years. Due to small sample sizes and the lack of adequate controls, no definite conclusions can be drawn from the available studies on the safety and efficacy of bariatric surgery (BS) in patients with IBD. Our aim was to assess safety, weight loss, and deficiencies in patients with IBD and obesity who underwent BS and compare findings to a control group. Methods Patients with IBD and a history of BS were retrospectively recruited to centers belonging to the Groupe d’Etude Thérapeutique des Affections Inflammatoires du Tube Digestif (GETAID). Patients were matched 1:2 for age, sex, body mass index (BMI), hospital of surgery, and type of BS with non-IBD patients who underwent BS. Complications, rehospitalizations, weight, and deficiencies after BS were collected in cases and controls. Results We included 88 procedures in 85 patients (64 Crohn’s disease, 20 ulcerative colitis, 1 unclassified IBD) with a mean BMI of 41.6 ± 5.9 kg/m2. Bariatric surgery included Roux-en-Y gastric bypass (n = 3), sleeve gastrectomy (n = 73), and gastric banding (n = 12). Eight (9%) complications were reported, including 4 (5%) requiring surgery. At a mean follow-up of 34 months, mean weight was 88.6 ± 22.4 kg. No difference was observed between cases and controls for postoperative complications (P = .31), proportion of weight loss (P = .27), or postoperative deficiencies (P = .99). Conclusions Bariatric surgery is a safe and effective procedure in patients with IBD and obesity; outcomes in this patient group were similar to those observed in a control population.

Background Preventive health measures reduce treatment and disease-related complications including infections, osteoporosis, and malignancies in patients with inflammatory bowel disease (IBD). Although guidelines and quality measures for IBD care highlight the importance of preventive care, their uptake remains variable. This systematic review evaluates interventions aimed at improving the rates of provision and uptake of preventive health measures, including vaccinations, bone density assessment, skin cancer screening, cervical cancer screening, and smoking cessation counseling. Methods We searched PubMed, MEDLINE, EMBASE, and CENTRAL for full text articles published until March 2021. Studies were included if they evaluated interventions to improve the provision or uptake of 1 or more preventive health measures in adult IBD patients and if they reported pre- and postintervention outcomes. Results In all, 4655 studies were screened, and a total of 17 studies were included, including 1 randomized controlled trial, 1 cluster-controlled trial, and 15 prospective interventional studies. A variety of interventions were effective in improving the rates of adherence to preventive health measures. The most common interventions targeted gastroenterologists, including education, electronic medical records tools, and audit feedback. Other interventions targeted patients, such as education, questionnaires, and offering vaccine administration at clinic visits. Few interventions involved IBD nurses or primary care physicians. Conclusions A range of interventions—targeted at gastroenterologists, patients, or both—were effective in improving the provision and uptake of preventive care. Future studies should involve randomized controlled trials evaluating multifaceted interventions that target barriers to adherence and involve IBD nurses and primary care physicians.

Background and Aims No consensus exists on defining intestinal ultrasound response, transmural healing, or transmural remission in inflammatory bowel disease, nor clear guidance for optimal timing of assessment during treatment. This systematic review and expert consensus study aimed to define such recommendations, along with key parameters included in response reporting. Methods Electronic databases were searched from inception to July 26, 2021, using pre-defined terms. Studies were eligible if at least two intestinal ultrasound [IUS] assessments at different time points during treatment were reported, along with an appropriate reference standard. The QUADAS-2 tool was used to examine study-level risk of bias. An international panel of experts [n = 18] rated an initial 196 statements [RAND/UCLA process, scale 1–9]. Two videoconferences were conducted, resulting in additional ratings of 149 and 13 statements, respectively. Results Out of 5826 records, 31 full-text articles, 16 abstracts, and one research letter were included; 83% [40/48] of included studies showed a low concern of applicability, and 96% [46/48] had a high risk of bias. A consensus was reached on 41 statements, with clear definitions of IUS treatment response, transmural healing, transmural remission, timing of assessment, and general considerations when using intestinal ultrasound in inflammatory bowel disease. Conclusions Response criteria and time points of response assessment varied between studies, complicating direct comparison of parameter changes and their relation to treatment outcomes. To ensure a unified approach in routine care and clinical trials, we provide recommendations and definitions for key parameters for intestinal ultrasound response, to incorporate into future prospective studies.

The interleukin-17 (IL-17) family consists of six family members (IL-17A–IL-17F) and all the corresponding receptors have been identified recently. This family is mainly involved in the host defense mechanisms against bacteria, fungi and helminth infection by inducing cytokines and chemokines, recruiting neutrophils, inducing anti-microbial proteins and modifying T-helper cell differentiation. IL-17A and some other family cytokines are also involved in the development of psoriasis, psoriatic arthritis and ankylosing spondylitis by inducing inflammatory cytokines and chemokines, and antibodies against IL-17A as well as the receptor IL-17RA are being successfully used for the treatment of these diseases. Involvement in the development of inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis and tumors has also been suggested in animal disease models. In this review, we will briefly review the mechanisms by which IL-17 cytokines are involved in the development of these diseases and discuss possible treatment of inflammatory diseases by targeting IL-17 family members., Graphical Abstract Graphical Abstract

Background Despite advancement in the treatment of inflammatory bowel disease (IBD), induction and maintenance of remission remain challenging to achieve in many patients and a significant proportion of patients with IBD experience mental health conditions, including anxiety, depression, and fatigue, which impair their quality of life (QoL). We aim to describe the available evidence regarding the effects of physical activity (PA) on the onset of IBD, its disease course, and important patient-reported outcome measures (PROMs), such as QoL, fatigue, and mental health. Methods A literature search was performed using electronic databases to identify original articles that assessed the effects of PA in patients with IBD using PROMs. Results Prospective cohort and case-control studies demonstrate inverse relationships between PA and new-onset IBD in Crohn’s disease but not in ulcerative colitis; however, they have small sample sizes and caution must be taken in considering associations versus causation. Small randomized controlled trials suggest promise for PA and beneficial outcomes, such as maintenance of clinical remission and improvement in QoL, fatigue, depression, and anxiety. However, these studies were small and underpowered, and limited by outcome measurements and durations of follow-up. Conclusions Physicians may consider discussing PA interventions with their patients on an individual basis, especially if they report impaired QoL, fatigue, depression, or anxiety, until disease-specific guidelines are available. Including PA as part of a primary prevention strategy in high-risk patients could be considered.

Background and Aims Age is a major prognostic factor for COVID-19 outcomes. The effect of inflammatory bowel disease [IBD] activity on COVID-19 is unclear. We examined the relationship between IBD activity and COVID-19 severity according to age. Methods We included IBD patients diagnosed with COVID-19, reported to SECURE-IBD between March 13, 2020 and August 3, 2021. Clinical IBD activity was measured by physician global assessment [PGA]. COVID-19-related outcomes were [1] intensive care unit [ICU] admission, ventilation or death, and [2] hospitalization. Using generalized estimating equations, we determined adjusted odds ratios [aOR, 95% confidence interval] for moderate and severe PGA vs clinical remission/mild PGA, controlling for demographics, medications and COVID-19 diagnosis period. We performed stratified analyses by age [≤50 vs >50 years]. Results Among 6078 patients, adverse COVID-19 outcomes were more common with active IBD: ICU/ventilation/death in 3.6% [175/4898] of remission/mild, 4.9% [45/920] of moderate and 8.8% [23/260] of severe [p < 0.001]; and hospitalization in 13% [649/4898] of remission/mild, 19% [178/920] of moderate and 38% [100/260] of severe [p < 0.001]. Stratified by decade, effect sizes were larger for younger patients. In patients ≤50 years, severe PGA was independently associated with ICU/ventilation/death (aOR 3.27 [1.15–9.30]) and hospitalization (aOR 4.62 [2.83–7.55]). In contrast, severe PGA was not independently associated with COVID-19 outcomes in those older than 50 years. Conclusions Clinically active IBD may be a risk factor for severe COVID-19, particularly in younger patients. IBD disease control, including through medication compliance, and strategies to mitigate the risk of COVID-19 infection amongst patients with active IBD [e.g. distancing, immunization] are key to limit adverse COVID-19 outcomes.

Care for patients with inflammatory bowel disease (IBD) can be complex and costly. Care delivery models to address these challenges and improve care quality are essential. The patient-centered medical home (PCMH), which was developed in the primary care setting, has recently been applied successfully to the adult IBD population. Following the tenets of the PCMH, this specialty medical home (SMH) emphasizes team-based care that is accessible, comprehensive, patient/family-centered, coordinated, compassionate, and continuous and has demonstrated improved patient outcomes. Children and young adults with IBD have equally complex care needs, with additional challenges not faced by the adult population such as growth, physical and psychosocial development, and transition of care from pediatric to adult providers. Thus, we advocate that the components of the PCMH are equally-if not more-important in caring for the pediatric patient population. In this article, we review what is known about the application of the PCMH model in adult IBD care, describe care delivery within the Center for Pediatric and Adolescent IBD at Nationwide Children's Hospital as an example of a pediatric IBD medical home, and propose a research agenda to further the development and dissemination of comprehensive care delivery for children and adolescents with IBD.This article summarizes the literature regarding the adult inflammatory bowel disease medical home, highlights the need for similar models in pediatrics using the Nationwide Children’s Hospital program as an example, and outlines next steps to support research and development of the pediatric IBD medical home.

BackgroundInflammatory bowel disease (IBD) is a chronic and debilitating illness associated with psychosocial comorbidities. Adolescents are vulnerable to the additive stress of managing IBD and navigating developmental milestones. Psychosocial factors, such as catastrophizing, illness stigma, illness uncertainty, and illness-related shame, often contribute to perceived stress in chronic illnesses. However, the combination of these variables on perceived stress in adolescents with IBD has not been examined.MethodsParticipants completed a cross-sectional online self-report survey. Model 4 of PROCESS Macro in SPSS was used to test the parallel mediation model of the relationship between disease severity and perceived stress using catastrophizing, stigma, uncertainty, and shame as mediators using 10,000 bootstrap samples. T-tests were run to assess systematic differences in the dependent variable between subjects.ResultsOne hundred and thirty-one adolescents (Mage = 18.95 years; 100 females) completed the survey. Females had higher stress scores than males (P =0.002), and there were no difference in stress between younger and older participants (P = 0.085), location (P = 0.484), or IBD type (P = 0.515). The total effect of disease stress on perceived stress operating through the mediators was significant, b = 0.168, SE = 0.028, 95% CI [0.112, 0.224]. Helplessness catastrophizing, illness uncertainty, and illness-related shame, but not illness stigma, were equally strong, positive mediators.ConclusionsThe present results suggest that helplessness catastrophizing, illness uncertainty, and illness-related shame are central elements to target in stress interventions for adolescents with IBD.

Observational studies provide evidence that metabolites may be involved in the development of autoimmune diseases (ADs), but whether it is causal is still unknown. Based on the large-scale genome-wide association studies (GWAS) summary statistics, we performed two-sample Mendelian randomization (MR) to evaluate the causal associations between human blood metabolites and multiple ADs, which were inflammatory bowel disease (IBD), ulcerative colitis (UC), crohns disease (CD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), multiple sclerosis (MS), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). After Bonferroni adjustment, we identified 6 causal features of metabolites, i.e., glycerol 2-phosphate for T1D, hexadecanedioate, phenylacetylglutamine and laurylcarnitine for RA, glycine and arachidonate (20:4n6) for CD. Comprehensive sensitive analysis was further performed to validate the robustness of associations. We also observed some overlaps of metabolites among different ADs, implying similar or shared underlying mechanisms in such pathogenic processes. Multivariable MR analysis was then conducted to avoid potential pleiotropic effect of other complex traits. After controlling for several common traits, multivariable MR analysis ruled out most of potential pleiotropic effects and validated independence of identified metabolites. Finally, metabolic pathway analysis was performed based on suggestive metabolites for each AD respectively and a total of seven metabolic pathways were identified. In conclusion, this study provided novel insights into investigating causal role of blood metabolites in development of multiple ADs through a comprehensive genetic pathway.

Mevalonate kinase deficiency should be considered in patients with severe very-early-onset inflammatory bowel disease (IBD), especially in patients with a history of recurrent or chronic fever, peritoneal adhesions, and atypical IBD pathology. Anti-interleukin-1 therapy may be efficacious in these patients with monogenic very-early-onset IBD.

Background The current burden of Crohn’s disease (CD) and ulcerative colitis (UC) in minority populations is largely unknown. We sought to evaluate the relative prevalence of CD and UC across racial and ethnic groups within the National Patient-Centered Clinical Research Network (PCORnet). Methods We queried electronic health records from 337 centers from January 2013 to December 2018. We compared the relative prevalence of CD and UC across racial/ethnic groups to the general PCORnet populations using χ 2 and univariable logistic regression. Results Among 39,864,077 patients, 114,168 had CD, and 98,225 had UC. Relative to the overall PCORnet population, Black adult patients were significantly less likely than White patients to have a diagnosis of CD (odds ratio [OR], 0.53; 95% CI, 0.52–0.54) or UC (OR, 0.41; 95% CI, 0.40–0.43). Pediatric Black patients were also less likely to have a diagnosis of CD (OR, 0.41; 95% CI, 0.39–0.43) or UC (OR, 0.38; 95% CI, 0.35–0.41). Adult Hispanic patients were less likely to have a diagnosis of CD (OR, 0.33; 95% CI, 0.32–0.34) or UC (OR, 0.45; 95% CI, 0.44–0.46) compared with non-Hispanic patients. Similarly, pediatric Hispanic patients were less likely to have a diagnosis of CD (OR, 0.34; 95% CI, 0.32–0.36) or UC (OR, 0.50; 95% CI, 0.47–0.53). Conclusions Despite the increasing racial and ethnic diversity in the United States, these data suggest that CD and UC are modestly less prevalent among patients of non-White races and Hispanic ethnicity.

Many diseases that affect modern humans fall in the category of complex diseases, thus called because they result from a combination of multiple aetiological and pathogenic factors. Regardless of the organ or system affected, complex diseases present major challenges in diagnosis, classification, and management. Current forms of therapy are usually applied in an indiscriminate fashion based on clinical information, but even the most advanced drugs only benefit a limited number of patients and to a variable and unpredictable degree. This ‘one measure does not fit all’ situation has spurred the notion that therapy for complex disease should be tailored to individual patients or groups of patients, giving rise to the notion of ‘precision medicine’ [PM]. Inflammatory bowel disease [IBD] is a prototypical complex disease where the need for PM has become increasingly clear. This prompted the European Crohn’s and Colitis Organisation to focus the Seventh Scientific Workshop on this emerging theme. The articles in this special issue of the Journal address the various complementary aspects of PM in IBD, including what PM is; why it is needed and how it can be used; how PM can contribute to prediction and prevention of IBD; how IBD PM can aid in prognosis and improve response to therapy; and the challenges and future directions of PM in IBD. This first article of this series is structured on three simple concepts [what, why, and how] and addresses the definition of PM, discusses the rationale for the need of PM in IBD, and outlines the methodology required to implement PM in IBD in a correct and clinically meaningful way.

Background Anxiety and depression are comorbid disorders with IBD and are associated with poor outcomes. Resilience is an innate but modifiable trait that may improve the symptoms of psychological disorders. Increasing resilience may decrease the severity of these comorbid disorders, which may improve IBD outcomes. The aim of this study was to describe the association between resilience, anxiety, and depression in IBD patients. Methods We performed a cross-sectional study of IBD patients. Patients completed a questionnaire consisting of the Connor-Davidson Resilience Scale (CD-RISC), a measure of resilience, the Generalized Anxiety Disorder 7 (GAD-7), and the Patient Health Questionnaire-9. Primary outcome was severity of anxiety and depression in patients with high resilience. Multivariable linear regression analysis evaluated the association between severity of anxiety and depression and level of resilience. Results A sample of 288 patients was analyzed. Bivariable linear regression analysis showed a negative association between resilience and anxiety (Pearson rho = −0.47; P < .0001) and between resilience and depression (Pearson rho = −0.53; P < .0001). Multivariable linear regression indicated that high resilience is independently associated with lower anxiety and that for every 1-unit increase in CD-RISC, the GAD-7 score decreased by 0.04 units (P = .0003). Unlike anxiety, the association between resilience and depression did not remain statistically significant on multivariable analysis. Conclusions High resilience is independently associated with lower anxiety in IBD patients, and we report a quantifiable decrease in anxiety score severity for every point of increase in resilience score. These findings suggest that IBD patients with higher resilience may have better coping mechanisms that buffer against the development of anxiety.

Background Clinical and molecular subcategories of inflammatory bowel disease (IBD) are needed to discover mechanisms of disease and predictors of response and disease relapse. We aimed to develop a study of a prospective adult research cohort with IBD (SPARC IBD) including longitudinal clinical and patient-reported data and biosamples. Methods We established a cohort of adults with IBD from a geographically diverse sample of patients across the United States with standardized data and biosample collection methods and sample processing techniques. At enrollment and at time of lower endoscopy, patient-reported outcomes (PRO), clinical data, and endoscopy scoring indices are captured. Patient-reported outcomes are collected quarterly. The quality of clinical data entry after the first year of the study was assessed. Results Through January 2020, 3029 patients were enrolled in SPARC, of whom 66.1% have Crohn’s disease (CD), 32.2% have ulcerative colitis (UC), and 1.7% have IBD-unclassified. Among patients enrolled, 990 underwent colonoscopy. Remission rates were 63.9% in the CD group and 80.6% in the UC group. In the quality study of the cohort, there was 96% agreement on year of diagnosis and 97% agreement on IBD subtype. There was 91% overall agreement describing UC extent as left-sided vs extensive or pancolitis. The overall agreement for CD behavior was 83%. Conclusion The SPARC IBD is an ongoing large prospective cohort with longitudinal standardized collection of clinical data, biosamples, and PROs representing a unique resource aimed to drive discovery of clinical and molecular markers that will meet the needs of precision medicine in IBD.

Background Fibrocytes are hematopoietic cells with features of mesenchymal cells found in the circulation and inflammatory sites implicated in promoting fibrosis in many fibroinflammatory diseases. However, their role(s) in the development of intestinal fibrosis is poorly understood. Here, we investigated a potential role of fibrocytes in the development of fibrosis in Crohn’s disease (CD) and sought factors that may impact their development and function. Methods Plasma and mononuclear cells were collected from patients with and without fibrostenotic CD. Fibrocytes defined as CD11b+, CD34+, and Collagen 1+ were correlated with clinical assessments of fibrosis, including evaluation using intestinal ultrasound. We measured the levels of relevant circulating molecules via Luminex and studied the effect of patient plasma proteins on fibrocyte differentiation. Results Fibrocyte numbers were increased in CD patients with stricturing Crohn’s disease compared with patients with an inflammatory phenotype (P = .0013), with strong correlation between fibrocyte numbers and acoustic radiation force impulse (ARFI), a measure of bowel elasticity on intestinal ultrasound (R = .8383, P = .0127). Fibrostenotic plasma was a more potent inducer of fibrocyte differentiation in both primary human monocytes and cell line and contained increased levels of cytokines implicated in fibrocyte differentiation compared with plasma from inflammatory patients. Interestingly, increased fibrocyte numbers at time of ultrasound were associated with escalation of medical therapy and endoscopic/surgical management of small bowel strictures at 30 months follow-up. Conclusions Circulating fibrocytes strongly correlate with fibrostenotic disease in CD, and they may serve as predictors for escalation of medical +/- surgical therapy.

Objective The association of IgA vasculitis (IgAV) and IBD is rarely described, mainly during anti-TNF-α therapy. We aimed to describe the association of IgAV and IBD. Methods We retrospectively analysed the association of IgAV and IBD through the implication of the GETAID and FVSG networks. Characteristics of IBD and IgAV were collected using a standardized case report form. Results Forty-three cases were included. IBD [mainly Crohn’s disease (CD) in 58%] preceded IgAV in 38 (88%), with median interval of 9.2 (IQR 5.4–15.4) years. In these 38 patients, at IgAV diagnosis, five (13%) had active IBD and 28 (74%) were treated with anti-TNF-α for a median duration of 31.5 (IQR 19–56) months. Main IgAV manifestations were purpura all patients (100%), joints in 20/35 (57%), renal in 15/35 (43%) and gastrointestinal in 11/35 (31%) involvement. IgAV was treated with glucocorticoids in 25 (66%), colchicine in six (16%), CYC in six (16%) and anti-TNF-α were discontinued in 15/28 (54%). No IgAV relapse occurred when TNF-α blockers were stopped, vs 23% in patients pursuing it. Conversely, five (33%) had IBD flare or complication after anti-TNF-α cessation vs one (8%) in those continuing biologics. Anti-TNF-α were resumed in six (40%), with subsequent IgAV relapse in four (67%). Conclusions This large cohort suggests that TNF-α blockers may promote the onset of IgAV in IBD. Discontinuation of anti-TNF-α was associated with vasculitis remission but increased risk of IBD relapses, whereas continuation of anti-TNF-α was associated with IBD remission but vasculitis relapse.

Background The first-in-class treatment PF-06480605 targets the tumor necrosis factor-like ligand 1A (TL1A) molecule in humans. Results from the phase 2a TUSCANY trial highlighted the safety and efficacy of PF-06480605 in ulcerative colitis. Preclinical and in vitro models have identified a role for TL1A in both innate and adaptive immune responses, but the mechanisms underlying the efficacy of anti-TL1A treatment in inflammatory bowel disease (IBD) are not known. Methods Here, we provide analysis of tissue transcriptomic, peripheral blood proteomic, and fecal metagenomic data from the recently completed phase 2a TUSCANY trial and demonstrate endoscopic improvement post-treatment with PF-06480605 in participants with ulcerative colitis. Results Our results revealed robust TL1A target engagement in colonic tissue and a distinct colonic transcriptional response reflecting a reduction in inflammatory T helper 17 cell, macrophage, and fibrosis pathways in patients with endoscopic improvement. Proteomic analysis of peripheral blood revealed a corresponding decrease in inflammatory T-cell cytokines. Finally, microbiome analysis showed significant changes in IBD-associated pathobionts, Streptococcus salivarius, S. parasanguinis, and Haemophilus parainfluenzae post-therapy. Conclusions The ability of PF-06480605 to engage and inhibit colonic TL1A, targeting inflammatory T cell and fibrosis pathways, provides the first-in-human mechanistic data to guide anti-TL1A therapy for the treatment of IBD.

Background Women with inflammatory bowel disease (IBD) have an increased risk of postpartum disease activity. We aimed to systematically determine the effect of various risk factors on postpartum IBD disease activity. Methods Electronic databases were searched through January 2021 for studies that reported risk of postpartum disease activity in women with IBD. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for the impact of IBD phenotype, disease activity, therapy de-escalation, mode of delivery, and breastfeeding on postpartum disease activity. Study bias was determined using the Quality in Prognostic Studies tool. Results Twenty-seven observational studies (3825 patients) were included, 15 of which had a high risk of confounding bias. The pooled incidence of women with postpartum active IBD was 31.9% (95% CI, 25.6–38.1). Similar results were seen with ulcerative colitis and Crohn’s disease (CD; OR, 0.96; 95% CI, 0.58–1.59). Those with stricturing (OR, 3.64; 95% CI, 1.31–10.08) and penetrating (OR, 4.25; 95% CI, 1.11–16.26) CD had higher odds of postpartum active IBD. Active disease at conception (OR, 10.59; 95% CI, 1.48–76.02) and during pregnancy (OR, 4.91; 95% CI, 1.82–13.23) increased the odds of postpartum disease activity. Similarly, biologic discontinuation in the third trimester (OR, 1.77; 95% CI, 1.01–3.10) and therapy de-escalation after delivery (OR, 7.36; 95% CI, 3.38–16.0) was associated with postpartum disease activity. Conclusions Complicated Crohn’s disease, disease activity at conception and during pregnancy, and de-escalation of biologics during pregnancy or after delivery are associated with postpartum disease activity in women with IBD.

Background Neurotrophic growth factors can stabilize the intestinal barrier by preventing the apoptosis of enteric glial cells (EGCs) and enterocytes. We reasoned that a selective 5-HT1A receptor agonist may have neuroprotective properties in the gut and that topical application of SR57746A might be an effective treatment strategy in inflammatory bowel disease (IBD). Methods The therapeutic potential of 5-HT1A receptor agonist SR57746A in IBD was evaluated in vitro (nontransformed NCM460 colonic epithelial cells, SW480 colorectal carcinoma cells) and in vivo (murine dextran sulfate sodium [DSS] colitis and CD4-T-cell transfer colitis). In vitro, we analyzed the effect of SR57746A on apoptosis in intestinal epithelial cells (IECs) and EGCs, and upon proliferation, migration, and intracellular signaling in IECs. In vivo, the effect of topical application of SR57746 on disease activity and on histological and endoscopic findings was compared with intraperitoneal infliximab and placebo, respectively. Results The SR57746A activates PI3-K/AKT- and ERK-signaling in IECs. Depending on ERK- and AKT activation, SR57746A potently prevents apoptosis of IECs without inducing proliferation or migration in these cells. Moreover, SR57746A prevented apoptosis in EGCs in vitro. Topical SR57746A treatment significantly reduced mucosal injury in 2 experimental murine colitis models and was as effective as intraperitoneal infliximab treatment. Conclusions Treatment with SR57746A prevents inflammatory cell damage and apoptosis in IECs and EGCs, similar to the neurotrophic effects of EGCs on IECs. Topical treatment with SR57746A could be a candidate for clinical evaluation in the treatment of IBD.

Background In cases of loss of response due to mechanistic failure under antitumor necrosis factor agents, it is recommended to switch to another class of biologics. Two different strategies were compared in patients with inflammatory bowel disease (IBD) who were treated with nonoptimized adalimumab (ADA) and experienced a loss of response despite therapeutic trough levels of adalimuma—either ADA dose optimization or switching to vedolizumab or ustekinumab. Methods Patients under maintenance therapy with ADA monotherapy (40 mg every 14 days) and who experienced a secondary loss of response with trough levels > 4.9 μg/mL were included prospectively in this nonrandomized study. The primary end point was the survival rate without therapeutic discontinuation after ADA dose optimization or switching to another class of biologics. Results Adalimumab was optimized (n = 61 patients, 42 Crohn’s disease, 19 ulcerative colitis) or swapped for vedolizumab (n = 40, 20 ulcerative colitis) or ustekinumab (n = 30, 30 Crohn’s disease). At 24 months, 11 out of 70 patients (14.8%) in the swap group discontinued treatment compared with 36 out of 61 (59.6%) patients in the optimization group (P 24 months) than in the optimization group (13.3 months, P 500 μg/g (HR, 3.53; 95% CI, 1.16–10.72; P = 0.026) and inversely associated with variation of trough levels of adalimumab (>2 µg/mL from baseline to week 8 after optimization; HR, 0.51; 95% CI, 0.13–0.82; P = 0.03). In the swap group, no factor was associated with treatment discontinuation. Conclusion In IBD patients under ADA maintenance therapy who experience a secondary loss of response and in whom trough levels are >4.9µg/mL, swapping to another class is better than optimizing ADA, which is, however, appropriate in a subgroup of patients.

Background Vaccination is a promising strategy to protect vulnerable groups like immunocompromised inflammatory bowel disease [IBD] patients from an infection with SARS-CoV-2. These patients may have lower immune responses. Little is known about the cellular and humoral immune response after a SARS-CoV-2 vaccination in IBD patients. Methods Totals of 28 patients with IBD and 27 age- and sex-matched healthy controls were recruited at Jena University Hospital. Blood samples were taken before, after the first, and in a subgroup of 11 patients after second dose of a SARS-CoV-2 vaccination. Cellular immune response, including IFN-γ and TNF-α response and antibody titres, were analysed. Results Overall, 71.4% of the IBD patients and 85.2% of the controls showed levels of anti-SARS-CoV-2 antibodies above the cutoff of 33.8 BAU/ml [p = 0.329] after the first dose. Even in the absence of SARS-CoV-2 antibodies, IBD patients showed significant T cell responses after first SARS-CoV-2 vaccination compared with healthy controls, which was not influenced by different immunosuppressive regimens. Associated with the vaccination, we could also detect a slight increase of the TNF production among SARS-CoV-2-reactive TH cells in healthy donorsn [HD] and IBD patients. After the second dose of vaccination, in IBD patients a further increase of humoral immune response in all but one patient was observed. Conclusions Already after the first dose of a SARS-CoV-2 vaccination, cellular immune response in IBD patients is comparable to controls, indicating a similar efficacy. However, close monitoring of long-term immunity in these patients should be considered.

Clostridioides difficile infection (CDI) in children with inflammatory bowel disease (IBD) can present and manifest differently from the general population with CDI, and it can worsen the underlying disease course. Furthermore, current clinical assays used to test for CDI do not accurately distinguish between true CDI or colonization. This uncertainty leads to difficulty in identifying the etiology and therapy for symptomatic patients with IBD. Improved diagnostic tests, biomarkers, and safe and effective treatment options are greatly needed for this vulnerable population.

Background Colorectal strictures have been considered independent risk factors for neoplasia in patients with inflammatory bowel disease (IBD). We examined the association between colorectal stricture and subsequent risk of colorectal neoplasia (CRN) in patients with IBD colitis undergoing colonoscopic surveillance. Methods We conducted a retrospective cohort analysis of patients with IBD colitis enrolled in colonoscopic surveillance for CRN at an academic medical center between 2005 and 2017. Inclusion criteria were IBD involving the colon for ≥8 years (or any duration with primary sclerosing cholangitis [PSC]) undergoing surveillance. Exclusion criteria were advanced CRN (ACRN; colorectal cancer [CRC] or high-grade dysplasia [HGD]) prior to or at enrollment, prior colectomy, or limited ( Results Among 789 patients with IBD undergoing CRC surveillance, 72 (9%; 70 with Crohn’s colitis) had a colorectal stricture on index colonoscopy. There was no significant difference in the frequency of ACRN or requirement for colectomy between patients with vs without a colorectal stricture (P > .05). Colorectal stricture was not associated with subsequent ACRN (adjusted odds ratio [aOR], 1.41; 95% CI, 0.49–4.07), CRN (aOR, 1.15; 95% CI, 0.51–2.58), or colectomy (aOR, 1.10; 95% CI, 0.65–1.84). Conclusions In this analysis of patients with IBD colitis undergoing CRN surveillance, the presence of a colorectal stricture was not independently associated with risk of ACRN or colectomy. Multicenter, prospective studies are needed to confirm these findings, particularly in patients with ulcerative colitis–associated colorectal stricture.

Background Several studies have reported an association between inflammatory bowel disease (IBD) and Parkinson’s disease (PD). The aim of this study is to re-evaluate for an association between IBD and PD while controlling for potential socioeconomic and environmental confounders. Methods We performed a retrospective cohort study using the Truven Health Marketscan database between January 1, 2005, and December 31, 2014. Individuals with IBD and household age-matched controls were identified. Adjusted hazard ratios (HRs) were calculated for the development of incident PD, adjusting for age, sex, residence type, US region, comorbidities, and behavior. Results In all, 154 051 subjects with IBD and an equal number of controls were identified. During a mean (SD) follow-up of 3.8 (2.2) years, 132 incident PD cases were identified. There was no significant association between IBD and PD (adjusted HR, 1.01; 0.72–1.42) when adjusting for the confounders previously mentioned. Conclusions We found no statistically significant association between these disorders. It is possible that previous associations identified between these disorders were confounded by environmental and socioeconomic factors.

Background Family studies support a genetic predisposition to inflammatory bowel diseases (IBD), but known genetic variants only partially explain the disease heritability. Families with multiple affected individuals potentially harbour rare and high-impact causal variants. Long regions of homozygosity due to recent inbreeding may increase the risk of individuals bearing homozygous loss-of-function variants. This study aimed to identify rare and homozygous genetic variants contributing to IBD. Methods Four families with known consanguinity and multiple cases of IBD were recruited. In a family-specific analysis, we utilised homozygosity mapping complemented by whole-exome sequencing. Results We detected a single region of homozygosity shared by Crohn's disease cases from a family of Druze ancestry, spanning 2.6 Mb containing the NOD2 gene. Whole-exome sequencing did not identify any potentially damaging variants within the region, suggesting that non-coding variation may be involved. In addition, affected individuals in the families harboured several rare and potentially damaging homozygous variants in genes with a role in autophagy and innate immunity including LRRK1, WHAMM, DENND3, and C5. Conclusion This study examined the potential contribution of rare, high-impact homozygous variants in consanguineous families with IBD. While the analysis was not designed to achieve statistical significance, our findings highlight genes or loci that warrant further research. Non-coding variants affecting NOD2 may be of importance in Druze patients with Crohn's disease.

Background Studies of adults with Crohn’s disease (CD) suggest that poor mental health precedes worsening disease activity. We evaluated whether depression and/or anxiety forecast worsening pediatric CD disease activity. Methods Through the Inflammatory Bowel Disease Partners Kids & Teens internet-based cohort, children with CD age 9 to 17 completed Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric measures and the short Crohn’s disease activity index (sCDAI). Using general linear models, we examined how baseline PROMIS Pediatric anxiety and depressive symptom scores independently associate with subsequent sCDAI scores (average survey interval 6.4 months). Models included baseline PROMIS Pediatric anxiety and depressive symptoms scores, baseline sCDAI, sex, age, parental education, race/ethnicity, and prior IBD-related surgery. We performed a post hoc subanalysis of children in baseline remission (sCDAI Results We analyzed 159 children with CD (mean age 14 years, 45% female, 84% in baseline remission). We found no association between baseline PROMIS Pediatric anxiety score and subsequent sCDAI (change in sCDAI for 3-point change in PROMIS Pediatric −0.89; 95% CI −4.81 to 3.03). Baseline PROMIS Pediatric depressive symptoms score was not associated with future sCDAI (change in sCDAI for 3-point change in PROMIS Pediatric Conclusion We found that neither anxiety nor depressive symptoms associate with subsequent disease activity in pediatric CD. These findings contrast with adult IBD studies, thus underschoring the unique pathophysiology, natural history, and outcomes of pediatric CD.

Objectives To investigate whether physical activity interferes with joint homeostasis in the presence of distant inflammation originating at barrier tissues such as skin or gut. Methods Eight-week-old male C57/Bl6 mice were treated with imiquimod cream on a shaved area of the back skin or with dextran sodium sulphate dissolved in the drinking water to induce psoriasis-like skin or inflammatory bowel disease-like gut inflammation. Afterwards, one group of mice was subjected to a 4-week forced running routine (n = 10 per group). Severity of cutaneous or intestinal inflammation was assessed clinically, by histology and by quantitative PCR. Knees and paws were analysed by micro-CT, histology, immunohistochemistry, second-harmonic generation microscopy and quantitative PCR. Results Local induction of inflammation triggered a systemic response with splenomegaly, loss of bone mass and bone marrow changes. Psoriasis- but not inflammatory bowel disease-like inflammation led to synovial lining layer hyperplasia, an increase in infiltrating CD45+ synovial cells, and suppressed entheseal extracellular matrix gene expression levels. Mechanical loading decreased the amount of F4/80+ synovial macrophages in untreated mice only and led to morphological alterations in the collagen fibres of the enthesis. Conclusion Systemic inflammation and mechanical loading act independently of each other. The former, originating from distant sites, can trigger mild synovial inflammation in mice, a propensity that may also impact the development of arthritis in patients; the latter has no impact on the severity of systemic inflammation, but independently affects joint homeostasis.