Evidence suggests there is an increased incidence of inflammatory bowel disease (IBD) in the psoriasis (PsO) population. However prior studies may have underestimated the degree of this association, by not considering (pre-)clinical markers or symptoms of IBD (e.g. elevated faecal calprotectin [FCal] and/or IBD red flags). Furthermore, patients with PsO are not typically screened for IBD. Here we describe the prevalence of IBD indicators in patients with moderate-to-severe PsO.

This was a multi-centre UK study of adults (≥18 years) with moderate-to-severe PsO. Patients were recruited from 12 primary care practices in Greater Manchester between November 2019 – April 2021 (in total, 983 eligible patients from an original cohort of 3485 were invited to participate). Retrospective review of primary care medical records was used to confirm a prior IBD diagnosis at baseline. For patients without a confirmed diagnosis, FCal monitoring and a bespoke questionnaire derived from validated measures of gastrointestinal (GI) symptoms and IBD red flags (CalproQuest IBD and Red Flag Index) were used to screen for IBD risk. Baseline interim data are presented as observed proportions, descriptive statistics, and counts along with 95% confidence intervals (CI).

252 patients were included: mean age was 57 (±15 SD) years and 54% were female (Table 1).


Use of non-steroidal anti-inflammatory drug therapy was reported by 15.5% of patients. In total, 64.7% (CI: 53.4−70.6%) of patients had ≥1 indicator of IBD risk at baseline (i.e., ≥1 of: IBD diagnosis, FCal ≥50 ɥg/g or ≥1 IBD red flag) and 3.6% (CI: 1.7−6.7%) of patients had a confirmed diagnosis of IBD. At baseline, 38.1% (CI: 33.5-46.1%) of patients had elevated (≥50μg/g) FCal (Table 2), and 34.9% (CI: 30.2−42.6%) of patients reported ≥1 IBD red flag. Both elevated FCal and GI symptoms were observed in 26.2% (CI: 21.8−33.5%) of patients.



Figure 1 depicts the overlap between different IBD markers in this cohort.

The risk of IBD in patients with PsO may be higher than previously reported. While 3.6% of patients in this cohort of patients with moderate-to-severe PsO had a confirmed IBD diagnosis, approximately two-thirds of patients exhibited at least one indicator of IBD risk (FCal ≥50μg/g and/or IBD red flag[s]). This study therefore highlights a population for whom further investigation to confirm IBD may be warranted. Prospective follow-up over the next two years will report on the outcomes of investigations, the final diagnoses and treatments in the identified ‘at risk’ cohort.

Background

Histological remission (HR) is evolving as a treatment target in ulcerative colitis (UC). Several histological indices have been developed, however, their widespread adoption beyond clinical trials is limited by practical difficulties and interobserver variability. Furthermore, the relative complexity of available scores hinders the development of an AI algorithm. We aimed to develop a simple histologic index, aligned to endoscopy, and apply it to a computer-aided diagnosis (CAD) system to evaluate HR.

Methods

614 digitalised biopsies (WSI) from 307 UC patients enrolled into a prospective multicentre study¹ were analysed. First, the simple PICASSO Histologic Remission Index (PHRI) based only on the presence of neutrophils, was developed and validated by expert pathologists. Table 1

To implement PHRI in a CAD system we designed a semi-supervised inductive transfer learning strategy composed of two modules. The first consists of a novel deep learning strategy based on a convolutional neural network architecture. This detected neutrophils in areas (patches) of a subset of 314 biopsies (172 remission, 142 active), in 158 of which the presence of neutrophils had been meticulously annotated at pixel level. WSI were then divided in training (172), validation (47), and testing sets (95). 

Following a multiple instance learning paradigm, a second model combined the features of all patches of each biopsy into a dichotomous result: presence/absence of disease activity. Figure 1 and 2. Finally, we compared the AI prediction with the pathologists’ assessment.

Results

PHRI correlated strongly with all endoscopic scores (MES, UCEIS and PICaSSO) of the same bowel areas (rectum and sigmoid) (Spearman’s ρ= 0.55 to 0.78). Inter-reader agreement between pathologists was almost perfect (ICC 0.84).

In the validation and testing sets our model predicted the presence of neutrophils respectively with 61% and 72% sensitivity, 98% and 84% specificity, 93% and 75% positive predictive value (PPV), and 86% and 83% negative predictive value (NPV) respectively (Table 2).

When predicting remission in whole biopsies, in the validation cohort the AI system had 65% sensitivity, 93% specificity, 86% PPV, and 78% NPV. In the testing cohort the same metrics were 62%, 94%, 90%, and 73% (Table 2).

Conclusions

PHRI is the simplest histological index in UC and correlates strongly with endoscopic activity. Based on PHRI we developed the first artificial intelligence model able to accurately predict histological remission in biopsies of UC. This tool can effectively expedite, support, and standardise the histological assessment of UC in clinical practice.

Reference:
1. Iacucci et al. Gastroenterology 2021

Patients undergoing colorectal surgery for inflammatory bowel disease (IBD) are recognized to have an increased risk of venous thromboembolism (VTE). The aim of this study was to determine the perioperative risk factors for VTE and to create a predictive scoring system for VTE in the IBD cohort.

The NSQIP-IBD registry from 2017-2020 was used to identify patients for the study.  Demographics, operative and outcomes data of IBD patients undergoing colectomies for IBD were analyzed. Student t and χ² tests were used for univariate analysis. A logistic multivariate regression model was performed using all significant variables to develop a predictive scoring system of VTE.

5003 patients (51.9% male, mean age 42.7, 57.3% Crohn’s / 42.7% ulcerative colitis) were included in the study.  125 (2.49%) developed VTE. The univariate analysis is presented in Table 1. On multivariate analysis ASA grade, ulcerative colitis, sepsis, serum sodium <139 mmol/L, an open abdomen and preoperative inter hospital transfer were associated with greater risk of VTE. An open abdomen postoperatively was associated with the highest odds of developing a VTE [2.69 (1.20 – 5.39, p=.009)].  Using these 6 significant factors, a risk model was created. The risk of VTE with one risk factor was 0.7% and 1.8% with two risk factors. The risk of VTE increased to 3.6% and 4.5% with three and four risk factors respectively. With five and six risk factors, the risk of VTE increased exponentially to 10.9%, 25% respectively (Figure 1).

This study affirms that multiple perioperative and operative factors increase the risk of VTE after surgery for IBD.  We present a novel model which demonstrates a cumulative risk increasing exponentially when more than five risk factors are present.

Etrasimod (ETR) is a once-daily, oral, selective sphingosine 1-phosphate receptor modulator in clinical development for immune-mediated inflammatory disorders including ulcerative colitis, Crohn’s disease, eosinophilic esophagitis, and atopic dermatitis. This study evaluated the single-dose bioequivalence of the proposed commercial and clinical formulations of ETR 2mg in the fasted state, and the effect of food on the pharmacokinetics of the proposed commercial formulation.

This 3-treatment, 3-period crossover Phase 1 study enrolled 18 healthy adults (18-55 years: 10 males/8 females). Participants were randomized to 6 treatment sequences (3 participants/sequence: ABC, BCA, CAB, ACB, BAC, CBA) consisting of Treatment A (single-dose ETR 2mg clinical formulation, fasted), Treatment B (single-dose ETR 2mg proposed commercial formulation, fasted), and Treatment C (single-dose ETR 2mg proposed commercial formulation, fed). Treatments were administered on Days 1, 10, and 19 to allow 8-day washout periods between treatments. In the fed state (Treatment C), all participants received an FDA-standard high-fat, high-calorie meal. Blood samples for determination of ETR concentration were collected at prespecified timepoints to 168 hours post dose. Analysis of variance was performed on log-transformed C_max, AUC_0-last, and AUC_0-∞ values to determine geometric least squares mean ratios (GLSMR) of Test/Reference and associated 90% confidence intervals (CI) to assess bioequivalence and food effects. Safety and tolerability of ETR were also evaluated.

 Bioequivalence: The 90% CI for the GLSMR of ETR C_max and AUC plasma exposure measures, comparing the proposed commercial vs clinical formulations, were within the accepted 80%–125% range (GLSMR and 90% CI) for establishing bioequivalence (Table 1). Median T_max for Treatments A and B were both 4 hours. Food Effect: The 90% CI for the GLSMR of ETR C_max and AUC plasma exposure measures, comparing the proposed commercial formulation under fed vs fasted conditions, were within the accepted 80%–125% range for establishing no food effect (Table 2). Median T_max for Treatment C was 6 hours. Safety and Tolerability: All treatment-emergent adverse events (AEs) were mild (except 1 moderate AE [headache]). One participant had an AE leading to study drug discontinuation. There were no serious AEs or deaths.

Based on results from this study, the proposed commercial and clinical formulations of ETR 2mg were bioequivalent in terms of rate and extent of absorption. No significant differences were demonstrated in ETR exposure for the proposed commercial formulation under fed and fasted conditions. All treatments were generally safe and well tolerated.

Fatigue is highly prevalent in patients with IBD independent of the disease status but treatment options remain limited. A potential mediator in the pathophysiology of fatigue is tryptophan (Trp), a precursor of serotonin. Recently, reduced serum Trp levels have been linked to fatigue in patients with clinically and endoscopically inactive IBD. The aim of the current study was to determine the effect of oral 5-hydroxytryptophan (5-HTP), the direct precursor of serotonin, supplementation on fatigue in patients with inactive IBD.

This multicentre, randomized, double-blind, cross-over, placebo-controlled trial included fatigued patients with IBD in clinical and biochemical remission (CRP <10mg/L, calprotectin <250 mg/kg), treated with immunosuppressants and/or biologicals. Fatigue was assessed with the fatigue VAS (fVAS, range 0-10) and defined by a fVAS ≥5. Patients were treated in a cross-over manner with 100 mg 5-HTP or placebo bid for two consecutive periods of 8 weeks, without an intermediate washout period. The primary endpoint was the proportion of patients reaching a 20% reduction in fVAS after 8 weeks of intervention (week 8 versus week 0 and week 16 versus week 8). Secondary outcomes were changes in validated FACIT-F score, scores for depression and anxiety and changes in Trp metabolites. The effect of the intervention on the outcomes was evaluated by linear mixed modelling (LMM), with the intervention, period and intervention x period as fixed factors and study participant as random factor.

A total of 166 patients were included in 13 Belgian centres between December 2018 and November 2020 (baseline characteristics: Table 1). The dropout rate was 10.8%. The evolution of the fVAS throughout the study was comparable between both study groups and no difference was observed in fVAS reduction between placebo and 5-HTP (Figure 1). The proportion of patients reaching ≥20% reduction in fVAS did not differ between placebo (37.6%) and 5-HTP (35.6%) (p=0.830). The evolution of the other scores for fatigue, depression, anxiety and stress were also similar between placebo and 5-HTP (Table 2). A significant increase in 5-HTP and serotonin serum levels was observed during 5-HTP treatment compared to placebo; whereas serum levels of Trp and kynurenine were comparable. Globally, changes in fVAS were not associated with changes in those metabolites (Figure 2). Adverse events (AEs) were seen in 29.2% and 34.8% of patients under treatment with placebo and 5-HTP respectively (p=0.282).

Despite a significant increase in serum 5-HTP and serotonin levels by oral treatment with 5-HTP, 5-HTP did not modulate IBD-related fatigue. Furthermore, treatment with 5-HTP had no impact on depression, anxiety and stress scores.

Background and Aims: 

Inflammatory Bowel Disease (IBD) impacts the individuals’ quality of life and affects all family members considerably. Previous reviews have focused on the impact of IBD on the patient, with limited exploration of the impact of IBD on family members. Therefore, this review aims to synthesise existing knowledge on the impact of IBD on family members, their coping strategies, the support needed, and interventions for family members to prevent and alleviate the burden of IBD. 

Methods: 
A systematic review using the mixed-method systematic review approach suggested by Joanna Briggs Institute (JBI) and the Preferred Reporting Items for Systematic Reviews (PRISMA) was undertaken. A systematic search of six bibliographic databases: MEDLINE, EMBASE, PsycINFO, CINAHL, British Nursing Index, and Web of Science, was performed in February 2021. The search focused on the impact of IBD on family members and coping strategies and interventions for this population. A narrative synthesis was conducted. 

Results:

In total, 3,258 records were identified, from which 33 relevant papers (2,748 participants) were included in the review, with case-control, cross-sectional, and qualitative designs. Synthesis of these papers found three themes: the impact of IBD on family members; the coping strategies for family members to overcome the negative impact of IBD; and the support needed. The IBD affects the family members in term of emotional well-being, fear and concern, relationship and social life, work and financial impacts, and leisure time and travelling. The coping strategy theme shows that family members use adaptive coping patterns such as acceptance, resilience, and emotional support from others. Maladaptive coping patterns such as denial following the initial relief of diagnosis, self-distraction, and self-blame were also used. In the theme ‘support needed’, family members reported the need for improved information about IBD, social support groups, self-help groups, educational meetings, and providing easy access to a counsellor or psychologist to support family members. There have been no studies assessing outcomes of interventions to relieve family members’ burden in the IBD population. 

Conclusion:

Our findings suggest that policymakers in healthcare services should emphasise the multidisciplinary professional care model such as a family therapist, IBD nurse, and psychologist. Researchers could incorporate a bio-psycho-social approach into their work on IBD to improve quality of life of both patients and their family members. 

1. To understand different kind of abstracts
2. To get knowledge about how to prepare an abstract 
3. To get knowledge about general rules and guidelines concerning abstracts
4. To get knowledge about how to prepare a poster from an abstract

The efficacy and safety of risankizumab (RZB) as induction and maintenance therapy forpatients with moderately to severely active Crohn’s disease (CD) has been documented. Steroid-free clinical remission is an important additional treatment goal in CD. The efficacy of RZB by baseline steroid use during induction and steroid-free outcomes during maintenance was examined.

In ADVANCE (NCT03105128) and MOTIVATE (NCT03104413), patients with moderately to severely active CD received intravenous (IV) RZB induction therapy or placebo (PBO) for 12 weeks. Patients with clinical response to RZB were re-randomised in a 52-week maintenance study (FORTIFY; NCT03105102) to subcutaneous (SC) RZB or PBO (ie, withdrawal). Patients receiving steroids (maximum prednisone or equivalent ≤ 20 mg/day; budesonide ≤ 9 mg/day) at baseline of the induction studies maintained stable doses for the 12-week study duration. A mandatory steroid taper per protocol was initiated at the beginning of maintenance for patients receiving steroids during induction. Patients losing clinical response (per investigator assessment) after initiation of taper could have their steroid dose increased up to the induction baseline dose. This analysis included patients who received RZB 600 mg IV in ADVANCE or MOTIVATE and patients who received RZB 360 mg SC in FORTIFY. Endpoints reported included clinical remission (defined by CD Activity Index [CDAI] or stool frequency/abdominal pain score [SF/APS] criteria) at week 12 of induction by baseline steroid use, steroid-free clinical remission (CDAI or SF/APS), steroid-free endoscopic response, and steroid-free endoscopic remission at week 52 of maintenance. Steroid discontinuation rates over 52 weeks of maintenance were also assessed.

Induction of clinical remission at week 12 with RZB 600 mg IV in ADVANCE or MOTIVATE was independent from baseline steroid use (Figure 1).Clinical remission rates (CDAI or SF/APS) at week 12 were similar for patients using steroids vs those who were not (33.8%–42.0% vs 34.9%–46.6%; Figure 1). Steroid use decreased over time in FORTIFY, with a greater proportion of patients receiving RZB 360 mg SC discontinuing steroids at week 52 vs withdrawal (PBO SC; Figure 2A). Rates of steroid-free clinical remission (P ≤ .012), steroid-free endoscopic response (P < .001), and steroid-free endoscopic remission (P < .001) were significantly higher with RZB 360 mg SC vs withdrawal (PBO SC) at week 52 of maintenance (Figure 2B–2C).

Efficacy of RZB induction therapy was independent of baseline steroid use. RZB maintenance promotes high rates of steroid-free clinical and endoscopic outcomes, demonstrating a benefit of RZB treatment in CD.

1. To understand adherence in a broad perspective
2. To review existing knowledge on adherence
3. To emphasize possible predictors for low adherence
4. To provide with some tools to measure adherence

Although characteristic findings within the mesentery have been described early on by Burrill Crohn himself, the role within Crohn’s disease has only partially been deciphered yet. Thus, this tandem talk will address the following three central points in the field:

1) Why this topic is of interest.

2) Reasons that suggest a protective role of the mesentery.

3) Reasons that suggest a disease-driving role of the mesentery.

This will be done by jointly discussing the available experimental, translational as well as surgical evidence. We will conclude by identifying the gaps in knowledge and by highlighting the ongoing clinical trials in the field.

1. to give a surgical point of view concerning adipose tissue and Crohn's disease

2. to present the reasons that underline a protective side of the mesentery, with the recent good results with KONO-S anastomosis (preservation of the mesentery) and stricturoplasty

3. to have an overview of the reasons that underline a disease-driven role of adipose tissue, with good results obtain with mesorectal resection during abdominoperineal resection for CD in Amsterdam and good preliminary results obtain by Coffey in Ireland with ileocecal resection with mesenteric resection for CD

4. to give an overview of the randomized trials in progress on mesenteric resection during ileocecal resection for Crohn's disease

Advanced endoscopic technologies led to significant progress in the definition of endoscopic remission of ulcerative colitis (UC), and correlate better with histological changes, compared to standard endoscopy. However, whilst studies have assessed the diagnostic accuracy of endoscope technologies individually, there is current limited data comparing between technologies. As such, we aimed to compare the correlations between endoscopy and histology disease activity scores across endoscope technologies

We searched PubMed and Embase in January 2021 for eligible studies reporting the correlation between endoscopy and histology activity scores in UC. Studies were grouped by endoscope technology as standard-definition white light (SD-WLE), high-definition white light (HD-WLE), or electronic virtual chromoendoscopy (VCE), and comparisons made between these groups

A total of N=27 studies were identified, of which N=12 were included in a meta-analysis of correlations between endoscopic and histological activity scores. Combining these returned a pooled correlation coefficient (rho) for the SD-WLE group of 0.61, which did not differ significantly from HD-WLE (rho: 0.79, p=0.140) or VCE (rho: 0.70, p=0.471) [Fig 1a]. In addition, N=4 studies reported the accuracy of endoscopic activity scores on WLE and VCE to diagnose histological remission. Pooling these found significantly higher accuracy for VCE, compared to WLE (risk ratio: 1.13, 95% CI: 1.07-1.19, p<0.001).[Fig 1b]

Activity scores assessed using endoscopy are strongly correlated with activity on histology. VCE appears to have better accuracy for the diagnosis of histological remission in UC, compared to WLE.

Histological remission is increasingly regarded as an important and deep therapeutic target for ulcerative colitis (UC). Assessment and scoring of histological images is a tedious procedure, that can be imprecise and prone to inter- and intra-observer variability. Therefore, a need exists for an automated method that is accurate, reproducible and reliable. This study aimed to investigate whether an artificial intelligence (AI) system developed using image processing and machine learning algorithms could measure histological disease activity based on the Nancy index.

A total of 200 histological images of patients with UC from a database at University Hospital, Vandoeuvre-lès-Nancy, France were used for this study. The novel AI system was used to fully characterise histological images and automatically measure Nancy index. The in-house AI algorithm was developed using state-of-the-art image processing and machine learning algorithms based on deep learning and feature extraction. The cell regions of each image, followed by Nancy index, were manually annotated and measured independently by 3 histopathologists. Manual and AI-automated measurements of Nancy index score were done and assessed using the intraclass correlation coefficient (ICC).

The 200-image dataset was divided into 2 groups (80% was used for training and 20% for testing). ICC statistical analyses were performed to evaluate AI tool and used as a reference to calculate the accuracy (Table 1). The average ICC amongst the histopathologists was 89.33 and average ICC between histopathologists and AI tool was 87.20. Despite the small number of image data, the AI tool was found to be highly correlated with histopathologists.

The high correlation of performance of the AI method suggested promising potential for IBD clinical applications. A standardised and validated histological AI-driven scoring system can potentially be used in daily IBD practice to eliminate the subjectivity of the pathologists and assess the disease severity for treatment decision.

Educational objectives:
1. To understand the role of IL-12 and IL-23 in the development of IBD
2. To review the pivotal UNITI and UNIFI trials
3. To review the place of ustekinumab in IBD therapy
4. To have an overview on practical modalities of ustekinumab therapy
5. To get insight in the anti-IL23 drugs that are in development

Educational objectives:
1. To understand the mechanism of action of vedolizumab and other anti interns
2. To review the key phase III clinical data
3. To highlight studies from real world cohort and discuss the safety profile of Vedolizumab
4. To understand how to position Vedolizumab in clinical practice

Educational objectives: 1. To understand the structural and functional features of the various anti-TNF agents, including originators and biosimilars 2. To review their use in Crohn's disease (CD), ulcerative colitis (UC) and in special indications 3. To have an overview of the optimal dosing of anti-TNFs, including therapeutic dose monitoring.

Anti-TNF were the first biological therapies available in IBD as well as in other immune-inflammatory disorders such as rheumatoid arthritis, spondyloarthritis and psoriasis. These agents can induce and maintain remission of CD and UC. They are also used in refractory pouchitis and microscopic colitis. Infliximab and adalimumab are approved in CD and UC, while certolizumab pegol is only approved for CD in some jurisdictions but not EU, and golimumab is approved for UC only. Biosimilars of infliximab and adalimumab are now available with all the indications of their originators. Data accumulate to support similar activity in both diseases, but some individual differences may be observed. Anti-TNF agents are increasingly used during pregnancy and for the treatment of extraintestinal manifestations of IBD.  Infliximab remains the best studied biological agent in IBD. The possibility of iv administration at high doses makes it the favored agent in fulminant colitis, fistulizing CD and in pyoderma gangrenosum. As all biological agents, anti-TNFS can induce anti-drug antibodies that represent the main cause of loss of response to these therapies. Continuous dosing beyond induction, combination therapy and premedication with hydrocortisone reduce this risk. Therapeutic dose monitoring and antibody detection are now available for all anti-TNF agents, the proactive use of which improves treatment outcome and preserves long-term response.

Discontinuation of anti-tumour necrosis factor alpha agents (anti-TNF) in patients with inflammatory bowel disease (IBD) in remission may reduce side effects and costs, but this has to be weighed against the risk of relapse. We developed a risk-stratified protocol for anti-TNF withdrawal, and aimed to assess the risk of relapse after risk-stratified anti-TNF withdrawal.

This was a single arm prospective observational cohort study. Patients were recruited between September 2018-2020 in 13 hospitals in the Netherlands. Inclusion criteria were a diagnosis of IBD, age >18 years, elective anti-TNF withdrawal in a patient with quiescent disease (according to the treating physician), no current or planned use of vedolizumab, ustekinumab or tofacitinib, no hospitalization, and no active or planned pregnancy. According to the protocol, patients were recommended to withdraw anti-TNF only when in endoscopic remission either without high-risk criteria (age at diagnosis <18 years, and for Crohn’s disease [CD]: smoking, stricturing/penetrating disease behaviour, small bowel resection >50cm), or when trough levels were undetectable. We constructed Kaplan-Meier curves with log-rank test to compare the risk of relapse in patients who discontinued anti-TNF in accordance with, versus against, the protocol. Cox regression analysis was performed to identify predictors of relapse.

We enrolled 115 patients (CD: n=61, 53%), with a median follow-up time of 1.9 (IQR 1.8 – 2.1) years. Baseline endoscopic remission was confirmed in 103 (89.6%) patients, and 35 (30.4%) patients continued an immunomodulator. During follow-up, 57 (49.6%) patients relapsed (Figure 1). The relapse rate was similar in patients in endoscopic remission who withdrew anti-TNF in according with, versus against, the protocol (50.7% versus 44.4%, p=0.65), and in patients with versus without an immunomodulator (hazard rate [HR] 0.89, 95%CI 0.50 – 1.59), but was lower in patients with subtherapeutic anti-TNF trough levels (adjusted HR: 0.55, 95%CI: 0.31 – 0.99), and in patients with UC/IBD-unclassified (IBDU) who were treated with mesalamine maintenance therapy (HR: 0.35, 95%CI 0.13 – 0.94). Anti-TNF was reintroduced in 41 (71.9%) patients, with remission rates of 64.5% and 81.8% at 3 and 12 months, respectively. In 6 (15.0%) patients anti-TNF therapy was discontinued again due to primary non-response or loss of response.

The risk of relapse after anti-TNF withdrawal remains high in a strictly selected group of patients with uncomplicated IBD in endoscopic remission. Therapeutic drug monitoring prior to anti-TNF withdrawal, and mesalamine therapy for patients with UC or IBDU, may reduce the risk of relapse.

Older adults are the fastest growing subpopulation of patients with IBD, with approximately 15% diagnosed after 60 years-of-age. Moreover, environmental exposures are thought to play a significant role in the development of older-onset IBD, given the lower genetic risk. Antibiotics have been associated with development of IBD in earlier generations, but the impact on IBD risk in older adults is uncertain. In this population-based cohort study, we assessed the impact of cumulative antibiotic use, the timing of antibiotic use, and the association between specific antibiotic classes and the development of older-onset IBD.

Using Denmark nationwide registries, a cohort of residents ≥60 years-of-age was established between 2000-2018. Information on exposure to antibiotics was retrieved from the Danish National Prescription Register. The number of courses of antibiotics (overall and specific classes) was considered a time-varying variable. The outcome, IBD, was identified based on ICD-10 codes in the Danish National Patient Register. Incidence rate ratios (IRRs) for IBD according to antibiotic use 1 to 5 years prior to IBD diagnosis were calculated by log-linear Poisson regression, and adjusted for age, sex, and calendar period.

There were a total of 2,327,796 individuals aged 60 to 90 years included in the cohort, resulting in 22,670,484 person-years of follow-up. There were 10,773 new cases of ulcerative colitis (UC) and 3,825 new cases of Crohn’s disease (CD). Overall, any antibiotic use was associated with an IRR for the development of IBD (IRR 1.64, 95%CI 1.58-1.71), with a positive dose response observed (1 course of antibiotics IRR 1.27 95%CI 1.21-1.33; 2 courses IRR 1.54 95%CI 1.46-1.63; 3 courses IRR 1.66 95%CI 1.67-1.77; 4 courses IRR 1.96 95%CI 1.83-2.09; 5+ courses IRR 2.35, 95%CI 2.24-2.47). A higher IRR was noted between the timeframe of 1-2 years before diagnosis (IRR 1.87, 95%CI 1.79-1.94) as compared to 2-5 years before diagnosis (IRR 1.42, 95%CI 1.36-1.48). Additionally, all antibiotic classes were associated with the development of IBD, including those not used to treat gastrointestinal infections. Antibiotics with the highest IRR were fluoroquinolones (IRR 2.27, 95%CI 2.08-2.48), nitroimidazoles (IRR 2.21, 95%CI 1.95-2.50), and macrolides (IRR 1.74, 95%CI 1.64-1.84). All results remained statistically significant when stratifying by UC and CD, with effect estimates slightly higher for CD as compared to UC.

Use of antibiotics, regardless of class studied, was associated with an increased risk of older-onset IBD. This risk was highest one to two years prior to diagnosis, but persisted even prior to that, suggesting a link between overall antibiotic use and development of older-onset IBD.

Antibody responses following SARS-CoV-2 infection or a single-dose of SARS-CoV-2 vaccine are impaired in patients with inflammatory bowel disease treated with anti-TNF compared to those treated with vedolizumab, a gut-selective anti-integrin α4β7 monoclonal antibody.  

Here we sought to determine if patients treated with infliximab have attenuated serological and T cell responses and an increased risk of breakthrough COVID-19 infection following primary SARS-CoV-2 vaccination. 

Anti-spike (S) receptor binding domain (RBD) antibody concentration in 2306 infliximab-treated patients were compared to a cohort of 1045 vedolizumab-treated patients. Our primary outcome was anti-S RBD antibodies 2 to 10 weeks after a second dose of the BNT162b2 or ChAdOx1 nCoV-19 vaccines. Secondary outcomes were anti-spike T cell responses, durability of vaccine responses and risk of breakthrough infections following two doses of vaccine.

Anti-S RBD antibody concentrations were lower in patients treated with infliximab than in those treated with vedolizumab, following a second dose of BNT162b2 (567.3 U/mL [6.1] vs 4601.1 U/mL [5.3], p <0.0001) and ChAdOx1 nCoV-19 (183.9 U/mL [5.0] vs 789.4 U/mL [3.5], p <0.0001) vaccines (Fig. 1).  

Vaccination with the BNT162b2 vaccine compared to the ChAdOx1 nCoV-19 was independently associated with a 3.7-fold [95% CI 3.30 – 4.13] higher anti-S RBD antibody concentration (p < 0.0001) (Fig. 2). 

There were no significant differences in the magnitude of anti-spike T cell responses observed in infliximab- compared with vedolizumab-treated patients after one or two doses of either vaccine.  

Antibody half-life was shorter in infliximab- than vedolizumab-treated patients following two-doses of BNT162b2 (4.0 weeks [95% CI 3.8 – 4.1] vs 7.2 weeks [95% CI 6.8 – 7.6]) and ChAdOx1 nCoV-19 (5.3 weeks [95% CI 5.1 – 5.5] vs 9.3 weeks [95% CI 8.5 – 10.2], p value < 0.0001).  

Breakthrough SARS-CoV-2 infections were more frequent (5.8% (202/3467) vs 3.9% (66/1691), p = 0.0032) and the time to breakthrough shorter in patients treated with infliximab than vedolizumab (p = 0.0023) (Fig. 3).  

Higher anti-S RBD antibody concentrations following a second dose of SARS-CoV-2 vaccine protected against breakthrough SARS-CoV-2 infection: overall, for every 10-fold rise in anti-S RBD antibody level we observed a 0.8-fold reduction in odds of breakthrough infection ([95% CI 0.70 – 0.99], p = 0.035).  

Infliximab was associated with attenuated, less durable vaccine induced anti-S RBD antibody responses and a 50% increase in breakthrough SARS-CoV-2 infection. Further follow-up is required to assess whether third primary doses can mitigate the effects of infliximab on anti-S RBD antibody responses.

Many papers in the past underpinned the possible role of appendicectomy. Appendectomy as a therapy for Ulcerative Colitis might work in mild ulcerative colitis. In the ACCURE, patients are randomized to medical therapy only or with appendectomy after induction of remission. Incidence of exacerbations is taken as primary endpoint. The first results will be available in one year time.

In the PASSION, patients with moderate to severe ulcerative colitis refractory to anti-TNF that were referred for colectomy were offered appendectomy. At 8 years follow up 1 out of three were colectomies, 1 out of three were having minor medication being biological free, and 1 out of five was on Tofacitinib. Endoscopic response was observed in at least in 1 out of 4. The Costa study is a patient preference model were patients are randomized or can choose either appendectomy of Tofacitinib when completely refractory to anti-TNF and Vedoluzimab. At this point 75% of the required patients are included.

There is accumulating evidence that appendectomy mitigates the disease course of ulcerative colitis