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Perianal fistulas are a common complication of Crohn’s disease (CD) affecting approximately 25% of patients, often predicting a more complicated disease course. Dysregulated immune responses and epithelial-to-mesenchymal transition (EMT) are hypothesised to contribute to fistulizing disease; however, they have been poorly studied. In this study, we investigated the immune phenotype of patients with perianal fistulizing disease and its relationship with tissue remodelling.

Immune cells were isolated from fistula curettage samples (n=31) and paired peripheral blood from patients with perianal Crohn’s (pCD) or idiopathic fistulizing disease. Multiparameter flow cytometry was performed to evaluate lymphocyte populations including invariant natural killer T-cells (iNKTs), gamma-delta (γδ) T-cells, CD161⁺ mucosal-associated invariant T-cells (MAIT), CD4⁺ T-cells and CD8⁺ T-cells. Gene expression profiling of fistula (Crohn’s n=11, idiopathic n=11) and rectal tissue (Crohn’s n=9, idiopathic n=9) was performed by RNA-sequencing. Cellular deconvolution of transcriptomic data using CIBERSORTx was performed to define the cellular phenotype of perianal fistulas. Cytokine treated intestinal epithelial organoids were used to probe the impact of selective cytokines on disease relevant pathways in perianal fistulas, using gene-set enrichment analysis (GSEA).

Perianal fistulas were characterised by expansion of iNKTs and CD4⁺ T-cells when compared to peripheral blood. Deeper analysis of the phenotype of these populations revealed enrichment of CD8^- CD4^- CD161⁺ iNKTs producing interleukin-22 (IL22), and CD4⁺ CD161⁺ T-cells producing interleukin-13 (IL13) and IL22. Surprisingly, pCD and idiopathic fistulas displayed similar immunophenotypes. Fistulas exhibited distinct transcriptional profiles to rectal tissue, although the phenotype of pCD and idiopathic fistulas appeared similar. Pathways related to the extracellular matrix (ECM) and EMT were more activated in fistulas compared to rectum. Gene-set enrichment analysis and cellular deconvolution identified an increase in the abundance of iNKTs, activated memory CD4⁺ T-cells, activated NK cells and neutrophils in fistula versus rectal tissue. IL13, IL22 and TNFα responsive transcripts were enriched in fistula tissue, and in the case of IL22, was shown to regulate key matrisome components. 

1. to have an overview over the incidence of proctectomy and perineal sinus in CD
2. to see the evidence on how perineal sinus may be prevented after proctectomy in CD
3. to see the evidence on the surgical treatment of a perineal sinus in CD
4. to understand one possible algorithm of treating a perineal sinus in CD

To understand the importance of perineal ultrasound in the diagnosis and follow up of Crohn's disease
To understand the technical aspects of perineal ultrasound
To understand the features of normal perineal ultrasound and of specifiec pathologies ( Fistula, abscess)

To understand the value of enhanced recovery pathways in improving patients' outcomes
To understand the key elements of succesful implementation of enhanced recovery pathways

Despite the proven efficacy of vedolizumab (VDZ), only 29% and 36% of the Crohn’s disease (CD) patients present corticosteroid-free clinical- and endoscopic remission, respectively. Therefore, predictive biomarkers for treatment success would be of extreme value. Previous studies have identified aberrant DNA methylation associated with CD-specific phenotypes, suggesting that the methylome may be useful for classification and prediction of VDZ treatment response. Here, we sought to identify such DNA methylation biomarkers that can predict clinical- and endoscopic response to VDZ in CD patients.

We prospectively recruited adult CD patients that initiated VDZ treatment following a baseline colonoscopy in two cohorts: a discovery and validation cohort. Peripheral blood DNA methylation profiles were measured prior to treatment (T1), and after a median of 22 weeks (T2) using the Illumina Infinium HumanMethylation EPIC BeadChip array. Response (R) was defined as the strict combination of endoscopic- (≥50% reduction in SES-CD score) and steroid-free clinical response (≥3 point drop in HBI and HBI ≤4 AND no systemic steroids) and/or biochemical response (≥50% reduction in C-reactive protein (CRP) and fecal calprotectin or a CRP ≤5 g/mL and fecal calprotectin ≤250 µg/g). Twenty-one patients had deep remission (DR), defined as a combined endoscopic- (SES-CD≤2) and steroid-free clinical remission (HBI ≤4, no systemic steroids). Biomarker identification and classification analyses were performed using stability selection gradient boosting.

In total, 64 CD patients were enrolled (discovery 16R/14NR and validation 20R/14NR). Both cohorts were comparable for age, sex and smoking status. Forty-nine (77%) patients had previously failed an anti-TNF agent. All patients had measurable serum vedolizumab concentration at T2 (median 14.5 (6.9 – 21.3) µg/mL).  Through classification analysis at T1, we were capable of discriminating R from NR with high predictive performance (25 CpGs, AUC 0.88, F1-score of 0.84, PPV of 0.91 and NPV of 0.85).  When analysing the methylome of patients in deep remission, we identified 23 CpGs with high predictive performance upon independent validation (F1-score 0.80, PPV of 0.71 and NPV of 0.86). Investigating the CpGs of interest implicated genes involved in endothelial cell-cell adhesion and integrin dependent T-cell homing, corroborating VDZ’s mode of action.

We demonstrate two novel 25- and 23-feature panels of epigenetic biomarkers that accurately predict response or deep remission to vedolizumab respectively. Similar analyses on infliximab, adalimumab and ustekinumab are currently ongoing as part of the EPIC-CD study.

1. To overview the current approaches for personalized nutrition in IBD
2. To discuss practical considerations when tailoring dietary recommendations to patients with IBD
2. To discuss challenges and future directions

To emphasize the potential for integration of treatment algorithms with prediction tools in IBD for the personalization of care
To recognize how current algorithms and prediction tools can be used to select biologics in IBD

Inflammatory bowel disease (IBD) exhibits heterogeneity at genetic, phenotypic, and therapeutic levels [1]. Although several studies have investigated genetic effects on IBD subtypes and drug adverse events [2,3], few have comprehensively explored the phenotypic and genetic determinants of IBD drug efficacy in a sufficiently powered cohort.

We used data from 32,199 patients in the UK IBD BioResource to investigate the effects of clinical phenotypes and demographics on drug efficacy and combined this with genome-wide genetic data for a subset of 11,536 individuals (Table 1). Drug efficacy was defined using a combination of clinician reported efficacy and persistence on drug without treatment escalation. Anti-TNF, thiopurine, steroids, and mesalazine were explored. We estimated phenotypic effects on drug efficacy using multivariable logistic regression and the genetic effects by genome-wide logistic regression. To explore whether drug efficacy and IBD disease susceptibility share a genetic basis, we estimated the proportion of variance in drug efficacy explained by known IBD risk variants [4]. Associations with Bonferroni corrected P-values < 0.05 were defined as statistically significant in phenotypic analyses and a genome-wide significance threshold of P=5x10^-8 was adopted for genetic analyses.

Drug efficacy was generally lower in patients with Crohn’s disease (CD) compared to those with other subtypes (OR ranges from 0.40 to 0.79), but anti-TNF showed a higher efficacy rate (OR = 1.21) in CD patients. Increasing age at diagnosis was associated with evidence of increased efficacy of thiopurine and mesalazine (Table 2). We found evidence of a genetic contribution to variation in drug efficacy for most drugs studied. However, known IBD risk variants showed little contribution (Figure 1). Using genome-wide association testing, we identified three loci showing a significant association with drug efficacy; two were related to steroid response and one to thiopurines (Table 3). None of these was an IBD disease susceptibility locus (P > 0.05).

Using a large, well-characterised cohort we found both genetic and phenotypic determinants of drug efficacy. Three loci were reported to be associated with drug efficacy in the first phase of the genetic analysis; at least 4,200 extra genotyped samples will be included before the ECCO meeting, thus increasing the power to detect additional loci. Our results suggest the genetic causes of drug efficacy and disease susceptibility are largely independent. These findings may provide opportunities for exploring the biology of drug efficacy and improving medication prioritization in IBD patients.

Reference
1. PMID: 16819502
2. PMID: 26490195
3. PMID: 30806694
4. PMID: 28067908

Educational Objectives:

1. Definition of point of care testing (POCT)

2. Patient´s view: why would I prefer POCT?

3. Fecal alprotectin (FC) – prototypic fecal marker of inflammation

4. Clinical studies assessing FC in POCT

5. Role of therapeutic drug monitoring

6. Effect of Covid-19 on POCT development

7. Lipocalin-2: a new fecal marker of inflammation

8. Outlook and challenges for POCT

Educational objectives:
1. To understand the growing prevalence of IBD in older people.
2. To understand the specific challenges in older patients relating to co-morbidities, polypharmacy and the limited data to guide care.
3. To understand the vulnerability of older patients to the effects of corticosteroids.
4. To discuss immunomodulators, biologics (and surgery) as options in the older IBD patient.
5. To consider carefully an individual's risk of infection, malignancy and their overall fitness in decision-making.

Mads Wewer reports on the analysis of population data from Denmark tracking the incidence and complications of peri-anal Crohn’s disease.

Perianal Crohn's disease (pCD) may present with a variety of lesions that include anal skin tags, anal canal lesions including fissures, ulcers, fistula and abscesses, strictures and cancer. pCD is disabling and aggressive phenotype that negatively impacts on the quality of life of affected patients. Perianal fistulas are common manifestations of pCD, with an incidence of 11 cases per 1000 patient-years. Successful treatment of pCD remains still a struggle for both physicians and patients. Significant advances in the management of pCD have occurred in the last two decades, resulting in the concept of a collaborative multidisciplinary approach using the latest medical therapies combined with modern surgical or endoscopic techniques. The use of antibiotics in the treatmentof pCD has limited evidence and antibiotics are currently used in combination with other therapies to prevent abscess formation and improve the rate of fistula closure. Thiopurines in pCD lacks of prospective trials, and evidence supporting their use should be carefully interpreted. Although anti-TNFs have revolutionized the prognosis for patients with pCD in the modern era, their effectiveness in the long term is limited: over 60% may relapse after one year of treatment and less than one third mantain sustained remission over time. Optimisation of anti-TNF treatment in pCD includes associaton with an antibiotic for the induction of fistula remission, combination with thiopurines to achieve appropriate anti-TNF trough level and a low likelihood of anti-drug antibodies. The use of vedolizumab and ustekinumab in pCD after anti-TNFs failure is mainly supported by one randomized phase IV trial (vedolizumab) and a number of real life reports (vedolizumab and ustekinumab), suggesting that they could be beneficial in patients who have failed to respond to anti-TNFs. Finally, in case of refractory pCD, a number of mesenchymal stem cell (MSC)-based therapies have been reported. In particular the use of darvadstrocel in refractory pCD is supported by phase 3 trial, showing that local treatment with adult allogeneic expanded adipose tissue-derived mesenchymal stem cells may succeed in 50% of treated patients after 6 months.