What is the optimal timing and methods for monitoring?

Educational objectives:
1. To understand the importance of disease monitoring in a treat-to-target strategy
2. To understand the difference between a treatment target and an instrument of tight disease control
3. To understand the need for a non invasive patient-friendly disease monitoring
4. To emphasize a proposal for a structured time-bound monitoring

 Disease monitoring is the corner-stone of a treat-to-target strategy. The definition of the treatment target is linked to our understanding of the disease process and the availability of markers to assess the disease process. Beside the target, we may define several steps to reach the target which are associated with specific tools and markers. Monitoring tools are not unique and must be articulated in a time-bound manner to allow an optimal disease control aiming at alleviating the symptoms and avoiding disease progression. In particular is a full endoscopic healing is currently the most widely accepted objective, intermediate steps may include symptomatic improvement and biomarkers improvement and normalization.

Up to 50% of Crohn’s patients develop intestinal strictures during their disease course. In general, predominant-inflammatory strictures are likely to benefit from anti-inflammatory medical therapy, whereas predominant-fibrotic strictures often require endoscopical/surgical approach. However, rarely is a stricture merely inflammatory or fibrotic; they are typically characterised by a mixture of inflammation, muscular hypertrophy, collagen disposition and fibrosis. Cross-sectional imaging techniques allow full-thickness evaluation of the bowel wall, of which IUS is non-invasive, cost-effective and can be used in the point-of-care setting, which makes is an attractive tool for monitoring.
The aim of the talk is to review the challenges of distinguishing inflammatory and non-inflammation strictures on conventional B-mode IUS and on advanced US modalities, such as CEUS and elastography.  

To understand imaging findigs of Fibrosis on cross sectional imaging with emphasis on MR-E 
To review litterature on MR-E and fibrosis
To have an overview over new imaging tools of Fibrosis (delayed enhancement, DWI, IVIM, Magnetization trasfert, Motility study).

Educational Objectives:
1. To appreciate the strong impact of the diet on gut microbial community structure and function
2. To understand the role of the diet in the pathogenesis of experimental gut inflammation
3. To review a role of the diet on the development and course of human inflammatory bowel diseases

1) Overview of the aetiology of IBD
2) Discussion of the impact of the environment on disease onset, course and response to therapy
3) Focus on the emerging evidence of a role of diet on disease onset from animal models, epidemiology and human studies
4) Discussion of the potential to modify the environment as a preventative strategy / therapy

Learning Objectives:
1. Screening before immunosuppression and immunisation
2. Indications for biological therapy
3. Evaluation of response

IBD patients are eligible to treatment with biologic agents if they have failed or cannot tolerate conventional treatment with corticosteroids and/or immunomodulators (IMMs) or are corticosteroid dependent. Early introduction of biologic therapy is also recommended for patients who at diagnosis have clinical features that predict a disabling course of disease. Ideally, patients should be screened for infectious diseases, malignancies, and complete all essential vaccinations before starting any therapy. Selecting the best biologic amongst the currently available different classes, depends on several patient- and disease-related parameters, such as age, disease activity, comorbidities, and the overall burden of disease. As for any therapy, it is important to define short-, medium- and long-term goals, monitor the progress of disease and adapt treatment accordingly (treat to target).

The first biologic is the best shot. Thus, it is key to adapt dosing to disease activity to avoid primary non-response or partial response and thus achieve a better long-term response. Co-treatment with an IMM may influence the pharmacokinetics in particular of anti-TNF and prevent early development of anti-drug antibodies ADA). Once clinical remission has been achieved, patients should be closely followed by monitoring clinical activity (patient reported outcomes), biomarkers (serum CRP, faecal calprotectin), imaging (US, MRE), endoscopy and/or histology. Treatment optimization in case patient loses response can be achieved either empirically (Standard of Care) by increasing the dose of the biologic or halving the administration interval, or both, or by adding an IMM, or by therapeutic drug monitoring (TDM), i.e., by measuring drug levels and ADA. Pro-active TDM has not been proven superior to reactive TDM, still, it serves to discriminate between pharmacokinetic and pharmacodynamic failure of treatment. However, proactive TDM is increasingly used to achieve clinical response and/or remission during induction, to de-escalate, or stop biologic therapy.

4. Screening before immunosuppression and immunisation
5. Indications for biological therapy
6. Evaluation of response

Educational objectives:
1. To understand growth impairment in paediatric IBD resulting from disease activity & treatment choices
2. To review the current ECCO/ESPGHAN treatment algorithm with regards to growth optimization
3. To provide an overview of strategies to minimize IBD activity-related growth impairment
4. To emphasise the importance of reducing steroid-exposure and improving skeletal growth and lean body mass

- understand approaches of using Omics-based medicine in other disciplines (oncology)
- review current mainstays in OMICS-based diagnostics
- get an overview of current trial designs on implementing omics into patient care

Combination therapy with infliximab and anti-metabolites is a standard option for patients with Crohn’s disease (CD). The implications of long term use of combination therapy may lead patients and clinicians to contemplate treatment de-escalation once steroid-free remission has been achieved. The aim of our study was to assess the relapse rates and time spent in remission over 2 years, after withdrawal of infliximab or anti-metabolite compared to continuation of combination therapy.

CD patients treated with a combination therapy of infliximab (IFX) and anti-metabolite > 8 months and in sustained steroid-free remission > 6 months were recruited in 64 centers in France, United Kingdom, Belgium, Sweden, Australia, Germany and The Netherlands. Patients were randomized into 3 arms - continuing combination therapy (arm A); stopping IFX (arm B); or stopping anti-metabolite (arm C). In case of a relapse [defined by CDAI and an objective marker of inflammation (CRP or fecal calprotectin)], patients were retreated by resuming infliximab in arm B or the anti-metabolite in arm C, according to a pre-defined scheme, including optimization of IFX up to 10 mg/Kg if necessary in all arms. The two co-primary endpoints were the relapse rate and mean survival time spent in remission over 2 years. A major secondary endpoint was treatment failure (complications or not recapturing remission).

254 patients were screened, 211 randomized, 5 withdrew consent and 1 was lost to follow-up, leaving 205 patients for the analysis - 67 randomized to arm A, 71 to arm B and 67 to arm C. Demographic and clinical characteristics are shown in Table 1. The two-year relapse rates were 14% (IC95%: 4-23%) in arm A, 40% (IC95%: 28-51%) in arm B, and 10% (IC95%: 2-18%) in arm C (p=0.0003 arm B vs arm A and <0.0001 arm B vs arm C) (figure 1). The time spent in remission was 1.91 yrs (IC95%: 1.83-1.99), 1.89 yrs (IC95%: 1.82-1.96) and 1.93 yrs (IC95%: 1.86-2.00) in arm A, B and C, respectively. Out of the 39 relapsers, 28 were retreated/optimized. Remission was achieved in 1/2 retreated patients in arm A, 22/23 in arm B and 2/3 in arm C.  Treatment failure was observed in 4/67, 4/71 and 3/67 patients, in these three arms, respectively. No malignancy was observed, one tuberculosis in arm C and two severe infections (pneumonia and viral pericarditis) in arm B.

Infliximab withdrawal, but not antimetabolite withdrawal, was associated with a significantly higher risk of relapse than continuation of combination therapy.  Almost all patients who stopped IFX achieved rapid remission when resuming treatment. The time spent in remission over 2 years was similar across groups.

1. To outline the multifactorial etiology of perianal CD
2. To describe advances in diagnosis in perianal CD over the last 10 years
3. To detail advances in medical and surgical therapy in perianal CD over the last decade
4. To understand the different therapeutic options for future management of perianal CD

1) To have an overview of the recent advances in surgery for ulcerative colitis
2) To understand the benefits of the laparoscopic approach for surgery in UC patients
3) to review the possible alternatives to pouch surgery in patients with UC: ileorectal anastomosis, appendectomy, ileostomy, segmental colectomy

Educational objectives:
1. To understand the role of 5-ASA in the treatment of IBD and the most frequent mistakes made in 5-ASA treatment
2. To review the evidence for dosing and treatment routes for the different localizations of inflammation in UC and CD
3. To emphasise the role of rectal 5-ASA therapy in proctitis and left sided colitis and the important role of oral/rectal combination therapy
4. To have an overview over optimal treatment strategies with 5-ASA

Organoids are self-renewing, 3D structures, consisting of different cell types, with histology and physiology features very close to the physiology of the studied organ. Specifically, human Intestinal Organoids (HIOs) develop epithelial crypts consisting of all subtypes of intestinal epithelial cells which are surrounded by mesenchymal cells. Our aim was to develop 3D HIOs from human embryonic stem cells (hESCs) and examine the expression of fibrotic and mesenchymal factors during their maturation process. Additionally, we investigated the effect of the pro-inflammatory cytokines, IL-1α and TNF-α on the expression of fibrotic and inflammatory mediators in HIOs.

The human ESC line (H1) was cultured and then differentiated towards HIOs using commercially available kit. HIOs were characterized by immunofluorescence in all differentiation stages. In order to examine their maturation process, we compared the mRNA expression of fibrotic and mesenchymal markers from passages 1-10. In order to examine their functionality, HIOs from different passages were stimulated with 5ng/ml IL-1α and 50ng/ml TNF-α for 12 hours, total RNA was collected and the fibrotic and inflammatory mRNA expression was examined. The mRNA transcripts of CD90, collagen type I, III, fibronectin, CXCL8, CXCL10 and CXCL11 were measured by reverse transcription quantitative PCR.

HIOs were successfully developed as they were stained positive for all tested markers throughout their developmental process. Regarding their maturation process, we observed high expression of CD90, collagen type I, type III and fibronectin that was gradually decreased during passages. As for the fibrotic and inflammatory responses from HIOs, we found that the IL-1α and TNF-α stimulation resulted in statistically significant upregulation of the fibrotic factors, fibronectin, collagen type I and type III in culture passages 2 and 4, but had no effect in culture passages 8 and 10. Similarly, IL-1α and TNF-α stimulation led to the statistically significant induction of the inflammatory chemokines CXCL8, CXCL10 and CXCL11 in culture passages 2 and 4, while no effect was observed in culture passages 8 and 10.

Our findings indicate that HIOs contain a functional mesenchymal component that is gradually diminished during passages. Inflammatory and fibrotic responses of HIOs seem to depend on the fitness of their mesenchyme. IBD studies using HIOs as in vitro models should be performed on early passages, when HIO’s mesenchymal component is still functional.

Accurately predicting disease course at diagnosis is critical to facilitate personalized therapy in inflammatory bowel disease (IBD). PredictSURE IBD^TM is a whole blood qPCR assay that was developed to predict prognosis in newly diagnosed, treatment-naïve IBD patients – classifying them into IBDhi (high-risk) or IBDlo (low-risk). The current recommendation is that PredictSURE IBD^TM should not be used in those who have commenced steroids. In this study, we aimed to determine the impact of steroid therapy on the performance of PredictSURE IBD^TM .

Whole blood was serially taken from patients admitted with severe IBD requiring intravenous (IV) steroids (pre-steroid, day 3, day 5; n=10, cohort 1) and from patients receiving oral steroids as outpatients (pre-steroid, week 1, week 6; n=10, cohort 2). An independent cohort of 43 IBD patients, all within 3 months of diagnosis and on corticosteroid treatment (41 systemic and 2 topical, cohort 3) was recruited. RNA was extracted and analyzed with PredictSURE IBD^TM (PredictImmune, UK). Patients were prospectively followed and treated according to routine clinical management by physicians blinded to the test results, and clinically stratified according to one of the original definitions used to construct and validate the test (need for step up to immunosuppressive or biological therapy or surgery).

In cohorts 1 and 2, both oral and intravenous steroids affected the PredictSURE IBD^TM result: misclassification as IBDlo occurred in 5/8 IBDhi patients receiving oral, and 5/7 IBDhi patients receiving IV, steroids. In 60% this change was detectable early (within 1 week of oral steroids and 3 days of IV steroids). Steroids did not affect the classification of IBDlo patients. Consistently, the prognostic accuracy was limited in patients already receiving steroids (cohort 3). After a median follow-up of 31.8 [IQR 18.7 - 42.1] months, 35 (81%) patients required step-up therapy. PredictSure IBD^TM correctly classified only 23 (54%) patients with accuracy of 0.53 (sensitivity: 0.51, specificity: 0.63, positive likelihood ratio: 1.38, negative likelihood ratio: 0.77). Seventeen (80%) of the misclassifications were clinically high-risk patients who were predicted as IBDlo. Time to treatment escalation was similar between patients classified as IBDhi or IBDlo after starting steroid therapy (p= 0.47) (Figure 1).

The prognostic accuracy of PredictSURE IBDTM is limited if performed after steroid therapy has begun, most likely because of the misclassification of high-risk patients as low risk. Therefore, the test should only be performed in patients with active disease who are not receiving steroid therapy, as currently recommended.

Local mesenchymal stromal cell (MSC)-therapy is approved for the treatment of Crohn’s disease-associated perianal fistulas. However, little is known about the working mechanism of local MSC-therapy. For the first time we evaluated engraftment and immunoregulatory effects of local MSC-therapy in patients with refractory proctitis. To do so, we analyzed biopsies and serum from patients with ulcerative proctitis before and after treatment with endoscopically injected MSCs in a phase IIa clinical trial (EudraCT number 2017-003524-75).

Thirteen therapy-refractory ulcerative proctitis patients were endoscopically injected bone marrow-derived allogeneic MSCs from healthy donors. Clinical efficacy was evaluated by the endoscopic and full Mayo score. Engraftment of the MSCs was investigated using fluorescence in-situ hybridization (FISH) of sex chromosomes on post-treatment biopsies. The presence of anti-HLA-antibodies against the MSC-donor was determined in the serum. Changes in immune cell subsets were evaluated using cytometry-by-time-of-flight (CyTOF) analysis.

Thirteen patients with an endoscopic Mayo score of 2 (n=3) or 3 (n=10) of the rectum were treated with local MSC-therapy. Although complete remission was not achieved, full Mayo score was improved at week 6 (median 8 [IQR 6-10]) compared to baseline (median 11 [IQR 9.5-12]) (p=0.001). Preliminary data using FISH on the Y-chromosome, indicated the presence of MSCs in the rectum biopsies of female patients treated with male donor derived-MSCs at week 6. At baseline, HLA-antibodies were present in four patients. Six weeks after local injection of the MSCs, two out of thirteen patients developed new class I and II HLA-antibodies against the MSCs. Interestingly, in two patients pre-existing HLA-antibodies showed increased/boosted levels after local MSC-therapy, while one additionally developed new HLA-antibodies. CyTOF analysis of inflamed rectal biopsies 6 weeks after MSC treatment revealed significantly increased frequencies of several myeloid subsets (i.e. CD11b+CD14+CCR7+/-CD127+CD25+HLADR+ and CD14+HLA-DR-CD123-CCR7+) and a subset of CD4+ memory T cells with a more exhausted/regulated phenotype (PD-1+TIGIT+CD69+CD38+CD69).

Local MSC-therapy in patients with refractory proctitis changed the rectal immune profile characterised by a significant increase in a subset of effector memory CD4+ cells and several myeloid subsets, which might be associated with immune modulation. These results provide the basis for future studies on the mechanism of action of MSCs on rectal mucosa. New anti-HLA class antibodies developed in 2/13 patients after local administration. Whether these latter results have consequences for MSC-donor selection deserves further study.

Measuring food-related quality of life (FRQoL) quantifies the psychosocial impact of eating and drinking.¹ The influences on FRQoL in people with inflammatory bowel disease (IBD) are not well explored, despite IBD being a chronic disease affecting the digestive tract. This study aimed to characterise and identify any patient or disease-related predictors of FRQoL in individuals with IBD.

Adults with a formal diagnosis of IBD were recruited to a prospective multi-centre cross-sectional study between April 2018 and December 2019. Participants completed questionnaires measuring FRQoL (IBD-FRQoL-29: minimum/poor 29, maximum/greatest 145), clinical disease activity (active disease: Harvey Bradshaw Index >4 active disease, Simple Clinical Colitis Activity Index >2, restrictive eating behaviour (Nine Item Avoidant/Restrictive Screen: minimum 0, maximum 45), mental health (DASS-21: minimum 0, maximum 126) and other patient and disease-related variables.

One hundred and eight participants completed the questionnaires. The majority of the cohort had UC (69/108, 64%) and there was almost equal distribution of those with quiescent (48%) and active (52%) disease The mean FRQoL of individuals with IBD was 79 (95% CI 75, 84) (see Figure 1). Poorer FRQoL was seen in those with restrictive eating behaviour associated with fear of a negative consequence from eating (p<0.0001) and reduced appetite (p<0.030). Greater FRQoL was seen in those with lower disease activity (p<0.0001) and previous IBD surgery (p=0.240). FRQoL was not influenced either way by IBD phenotype, duration, or gender. The majority of participants obtained their dietary information from the internet (60%) or gastroenterologist (46%).

FRQoL in people with IBD is poorer in those with restrictive eating behaviours and clinically active disease.  Interestingly, it was greater in those with previous IBD surgery. Further research is required to validate these associations and explore longitudinal effects of poor FRQoL on patient outcomes and potential strategies for prevention or management of impaired FRQoL in IBD.


References
¹Hughes LD, King L, Morgan M, et al. Food-related quality of life in inflammatory bowel disease: Development and validation of a questionnaire. J Crohns Colitis 2016;10:194-201.

The prevalence and risk of Eating Disorders (ED) in IBD, despite the potential overlap of these two conditions, have been rarely reported. ED diagnosis should be considered in patients with IBD and multidisciplinary approach would be recommended in these complex cases to provide an adequate therapeutic intervention. Screening tools to evaluate eating attitudes and behaviours in patients with IBD could be used in daily practice, as for example the Eating Attitude Test – 26

Children and adolescents (8-18 years) with IBD and age and gender matched healthy controls were prospectively enrolled in 5 italian pediatric IBD units between June 2019 and August 2020. Subjects with an existing diagnosis of ED were excluded. The risk of ED was assessed using a 26 points Likert scale screening tool (CH-EAT-26 and EAT-26 for children < and > 14 years respectively), with a total score of 20 or above indicating a risk for ED. Correlations between clinical and disease’s parameters and the CH-EAT-26/EAT-26 score were calculated

110 patients with IBD and 110 age and matched healthy controls were screened with the CH-EAT26/EAT-26 questionnaire. The total EAT26 scores and the prevalence of an at-risk score (score>20) did not differ in IBD subjects compared to controls. IBD patients were more frequently on an exclusion diet with lactose free-diet being the most common regimen. Furthermore, 8.1% of IBD children was on a partial enteral nutrition (PEN). In IBD subjects elevated scores on the Ch-EAT26/EAT-26 were associated with being younger (r=-0,2226, p=0.002), following an exclusion diet (r=0.25, p=0.009) and a partial enteral nutrition (PEN: r=0,2507, p=0.009). Type, duration and activity of disease, gender, weight, height and BMI z-scores were not significantly correlated to the CHEAT26/EAT-26 score. Being on a PEN  and  following an exclusion diet were the only independents factors influencing the EAT26 score at the multiple regression analysis (p= 0,004; p= 0,034; R2 = 0,25)

Our results indicate that 5.45% of IBD children have a behavior at risk for developing an ED, a percentage that is not statistically different compared to healthy controls. A particular follow-up should be reserved to patients on restricted diets and on partial enteral nutrition, that can develop maladaptive attitudes toward eating. The development of a disease specific tool or a validation of pre-existing questionnaires would help to identify a robust screening instrument and ultimately to correctly classify the risk of patients. Once the risk is correctly assessed it is mandatory to address the patient to a specific multidisciplinary follow-up.

Recent progress in deciphering the complex pathogenesis of Crohn’s disease (CD) has yielded several effective biologicals. However, ambitious therapeutic goals remain unfulfilled as almost 30% of patients are primary non-responders to a particular biological. This underscores the need for easy-to-implement biomarkers that predict (non-)remission. We aimed to identify serum protein biomarkers that predict endoscopic remission in CD patients.

Serum samples from 169 consecutive CD patients with active endoscopic disease (presence of ulcerations) before starting a biological [infliximab (IFX), adalimumab (ADA), vedolizumab (VDZ) or ustekinumab (UST)] to which they were naïve were collected. Patients were prospectively followed with endoscopic re-assessment after 6-12 months. There were 102 patients (Table 1) with endoscopic remission (SES ≤ 2 or disappearance of all ulcers), whereas 67 showed no improvement. Two independent and complementary proteomic platforms were used: 644 proteins belonging to predesigned assays were quantified using Proximity Extension Assay (PEA) technology (Olink Proteomics AB, Sweden). Second, wide protein discovery mass spectrometry (MS)-based technic (Caprion, Canada) was used and quantified another 985 proteins. A multivariate modelling framework was then applied on a randomly selected training sub-cohort (85%). Predictive performance of identified panels was assessed on the remaining test sub-cohort (15%). We sought to implement the same framework on the drug-specific subgroups; however, train/test splitting was not possible in IFX or ADA subgroups due to very few observations in the non-remission arms which diminishes the possibility for reliable predictive modelling.

Applying the modelling framework on training sets from the general cohort, VDZ subgroup and UST subgroup, proteomic panels were selected and consisted of 26, 6 and 8 proteins, respectively, and showed high performance in the test sets (Table 2).  VDZ and UST panels shared only 2 proteins each with the general panel, and had no predictive power (accuracy ≤ 0.5) when used to predict other subgroups, making them specific to their respective drugs. Selected proteins are involved among others in pro-inflammatory, extracellular matrix modelling, coagulation and cellular-vascular interaction pathways (Table 3).

Applying a multivariate machine learning algorithm on a wide pool of serum proteomics analysed through two discovery technics, we were able to identify 3 proteomic panels that can predict endoscopic (non)remission in patients with CD. Exact implication of these proteins in intestinal inflammation and a validation in an independent cohort is being further investigated.

Ulcerative Colitis (UC) associated single nucleotide polymorphisms (SNP) are mostly in non-coding regions of the genome. Because of that, it has been challenging to determine their role in the disease onset and severity. We have previously developed an integrative workflow (termed iSNP) to understand better how these SNPs are involved in the pathogenesis of UC. Here we present a recent update both in the methodology and new results, including a new player for prediction of therapeutic escalation in UC.

From immunochip data of 376 UC patients of an East-Anglian, UK cohort, the SNPs were filtered for only the UC-associated ones. Then we predicted the SNPs’ effect on regulatory interactions using two complementary transcription factor-target gene prediction methods, RSAT and FIMO. SNPs were considered if the SNP was located in the promoter region of a gene or in an enhancer region of a gene defined by the HEDD database. We considered a gene ‘SNP-affected’ if the risk allele and the non-risk allele had different transcription factor binding sites detected by any of the two methods. The proteins encoded by the SNP-affected genes were mapped to the integrated and high-confidence signaling network resource OmniPath. We also identified the direct physical interactors (first-neighbours) of these SNP affected genes/proteins. We created networks for each patient separately using their individual SNP-profiles. Finally, based on these patient-specific networks, we clustered patients in an unsupervised manner.

We found 15 UC-associated SNPs which affected transcription factor binding sites, which in turn were modulating 54 genes. From these 54 SNP affected genes, 29 coded proteins that were present in the OmniPath signaling network. The patients formed five clusters, which were significantly correlated with therapeutic escalation defined by mesalazine or other more advanced therapy (p <0.05). Patients requiring immunomodulatory treatment have a greater prevalence of  SNP RS943072 (G), corresponding to the transcriptional regulation of VEGF (vascular endothelial growth factor). VEGF is elevated in UC and stimulates angiogenesis, which is involved both in tissue regeneration and inflammation. VEGF is upregulated in the presence of this risk SNP causing increased inflammatory phenotype.

We updated the iSNP method by including enhancer regions and multiple transcription factor binding site prediction methods, and were able to predict that those UC patients who have a VEGF-affecting SNP require therapeutic upscaling.