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IBD diagnosis7th H-ECCO IBD Masterclass
Year: 2022
Authors: Ann Driessen
Summary content

Paediatric onset IBD represents approximately 20 to 25% of cases of IBD. Paediatric onset IBD is subclassified based on age, namely paediatric IBD (10-16 yrs), early onset IBD (6-10 yrs) and the very early onset IBD (younger than 6 yrs). The last group comprises two very young age groups, namely neonatal ( < 28 days) and infantile IBD (1 mo-2yrs). The prevalence of very early onset IBD varies between 3-15% of all pediatric IBD. Very early onset IBD is a heterogeneous disease with a clinical presentation different from adult IBD. Morphologically there are different patterns described, of which the active chronic enteritis show some resemblance with the classical IBD.  In time the morphological features may be become more obvious to diagnose IBD. The other forms shows some morphological features suggestive of a monogenic form of very early onset IBD, such as apoptosis.Clinically the disease is characterized by a more aggressive course with increase in severity, frequently resistant to the standard therapy. In these circumstances genetic counselling is necessary to exclude monogenic forms of very early onset IBD. These diseases require a specific treatment in function of the defect either at the level of the intestinal barrier or in the immunesystem, resulting in different types of immune deficiencies .

IBD differential diagnosis7th H-ECCO IBD Masterclass
Year: 2022
Authors: Ann Driessen
Summary content

The characteristic histological features of inflammatory bowel disease are a disturbed crypt architecture, basal plasmacytosis and granulomas. Numerous diseases may clinically as well morphologically mimic IBD. Hence to make a diagnosis of IBD close communication between clinicians and pathologists is essential. Different types of infections are mimickers of IBD, such as Yersinia, Entamoeba histolytica. An important mimicker, which may give rise to a differential diagnostic problem, is tuberculosis. The incidence of tuberculosis is rising due to immigration, immunodeficiencies, the use of immunomodulators, … Distinction between Crohn’s disease and tuberculosis is essential as treatment is totally different. Differentiation is based on its clinical presentation, morphology and may be confirmed by different ancillary techniques. A main feature is the presence of granulomas in the biopsy or the wall of resection specimen. Different diseases, restricted to the gastrointestinal tract or systemic, are associated with granulomas in the intestine. Hence the presence of a granuloma implies an extensive differential diagnosis.   

IBD is team work6th Basic ECCO: EduCational COurse for Industry
Year: 2022
Authors: Geert D'Haens; Willem Bemelman; Maria Louise de Jong - van der Zee
Summary content

IBD are chronic, life-long disorders associated with complex medical, surgical and psychosocial issues. Therefore, IBD clinics need to have a multidisciplinary team to discuss and strategize the most challenging cases. This will enhance quality of care and may reduce disease burden and morbidity. In this session, the IBD nurse practitioner, gastroenterologist and colorectal surgeon will discuss two challenging cases where teamwork is essential.

Educational objectives
1. To have an overview of the multidisciplinay team
2. Basics fistulizing Crohn's disease and acute severe ulcerative colitis
3. To understand the multidisciplinary approach

IBD: Epidemiology, Immunopathogenesis, and their relevance to therapeutics20th IBD Intensive Course for Trainees
Year: 2022
Authors: Iris Dotan
Summary content

1. To review recent epidemiologic data, highlighting the importance of environmental factors
2. To understand the complexity and multiple factors contributing to IBD pathogenesis
3. To acknowledge how the complexity of IBD may affect treatment effects

Identification and characterization of T-cell receptor sequences associated with Crohn’s DiseaseECCO'22 Virtual
Year: 2022
Authors: Matthieu Allez
Background

T cells, as part of the adaptive immune system, are a significant driver of inflammation in Crohn’s disease (CD), yet specific T-cell targets are largely unknown. Genetic factors contribute to a small portion of CD risk including several HLA alleles, such as DRB1*07:01 and HLA-DRB1*01:03, associated with CD. The involvement of HLAs suggests that studying specific T cells could lead to new insights into CD development and progression. In this study, we use established immunoSEQ® technology to profile T-cell receptors (TCRs) and identify TCRs associated with CD and CD characteristics.

Methods

We analyzed TCRs from blood of 1,738 CD cases and 4,970 healthy controls. TCRs that were statistically enriched in cases, but not healthy controls (p <0.001), were termed Enhanced Sequences (ES) associated with CD. An independent cohort of 434 CD cases was used for validation. We inferred associations between the ES and 145 common HLA alleles using data from a separate, HLA-typed dataset. We defined ES clusters by correlating TCRs with single amino acid substitutions.

Results

We identified 1,121 CD-associated ES in the exploratory cohort. These were also enriched in CD cases in our validation cohort (Fig 1A). Using intestinal tissue samples from a subset of cases, we found that a median of 14% ES from individual cases were shared between blood and tissue samples (Fig. 1B). ES breadth (ES diversity relative to total TCR diversity) was significantly associated with history of CD-related surgery (Fig 1C, p < 1x10-15), with stricturing or fistulizing phenotypes (Fig 1D, p < 1x10-5 for B1 versus B2 or B3), and with ileal or ileocolonic location (Fig 1E, p < 1x10-7 for L2 versus L1 or L3).

We found that 202 ES formed clusters of similar sequences consisting of 2-23 members (Fig. 2A). We confidently (p < 0.0001) associated 398 ES to a specific HLA allele (Fig 2B), including 134 of the ES assigned to clusters (Fig 2A). Some clusters, including the largest, had no members that could be assigned to an HLA allele, raising the possibility that these ES clusters bind non-canonical HLAs.

Conclusion

Our discovery set of public TCRs associated with CD indicates that the immune system of CD patients responds to a consistent set of antigens. Importantly, CD ES were present in both tissue and blood, demonstrating that evaluating TCRs in blood may be a surrogate of TCRs in tissue. The HLA allele associations of these ES potentially point to new risk factors and disease insights, such as the involvement of DP and DQ alleles. The association of ES frequency with CD characteristics strongly suggested that further examination of these TCRs may impact CD patient care and advance understanding of the pathophysiology of the disease.



Identification and development of a 1st in class naturally-derived protein that drives mucosal healing and is orally delivered by an engineered cellular therapy targeting the gastro-intestinal tractECCO'22 Virtual
Year: 2022
Authors: Joe Dal Porto
Background

In Inflammatory Bowel Disease (IBD), intestinal barrier dysfunction and epithelial cell injury are believed to be associated with activation of the immune system to drive disease-associated inflammation, which together constitute key features of active disease. Existing drugs used to treat IBD induce endoscopic remission and improvements in mucosal healing  in only a minor proportion of patients, driving a critical need for therapies which lead directly to mucosal healing. Furthermore, predicting patients who may benefit from therapeutics that address specific mechanisms of mucosal healing may augment response rates.

Methods

We screened proteins, identified from a meta-analysis of healthy human microbiome, in cellular assays and animal models related to mucosal injury, with the goal of identifying novel therapeutics that have the potential to directly induce mucosal healing. The proteins identified were further optimized by protein engineering to increase their stability as well as gastro-intestinal (GI) targeting via oral administration. For this, therapeutic proteins were expressed using a probiotic, Lactococcus lactis (L.lactis), engineered to display the recombinant proteins on the cell surface, and evaluated for activity in DSS- and DNBS-induced models of colitis in mice. Mechanism of action studies using computational and laboratory based methods to analyze gene expression and direct molecular interactions with human proteins, enabled the identification of pathways modulated by the candidate molecules. These pathways were further evaluated for their ability to identify biomarkers in specific patients most suitable for treatment in a precision medicine approach.

Results

We have identified a novel, healthy microbiome-derived protein that demonstrated robust activity in human epithelial injury assays in vitro. The protein reduced intestinal injury related pathology in mice when orally administered to target directly the GI tract. SG-5-00455, the product based on an L.lactis strain expressing the candidate therapeutic protein, reduced pathology scores, inflammation and barrier function related LPS-binding protein levels to levels comparable to those obtained glucagon-like peptide 2 (GLP-2), as well as improving dysregulated tissue repair and fibrosis-associated gene expression and proteins levels.  SG-5-0455 treatment did not result in systemic exposure, driving its therapeutic activity in a GI-localized manner by targeting pathways related to tissue injury and fibrinolysis.

Conclusion

SG-5-00455, through its novel mechanism of action and oral delivery to directly target tissue repair pathways in the GI-tract, offers the potential to address a large critical need in IBD.

Identification of an intestine-derived ex-Trm population in the blood of healthy individuals and patients with Inflammatory Bowel Disease8th Y-ECCO Basic Science Workshop
Year: 2022
Authors: Beverley Rodger
Background

Tissue-resident memory T cells (Trm) persist in peripheral tissues and contribute to pathogen clearance and inflammation. Trm can re-enter the circulation (ex-Trm) and give rise to new effector and Trm populations. Skin-derived ex-Trm can be identified in human blood based on co-expression of the residency marker CD103 and cutaneous leukocyte antigen (CLA), a skin-tropism marker. The existence of ex-Trm derived from the gut would have implications for inflammatory bowel disease (IBD) and its treatment targeting the recruitment of circulating gut-homing cells.


Methods

Peripheral blood and colonic biopsies were taken from healthy volunteers and patients with IBD (Crohn’s disease or ulcerative colitis). PBMCs and cells isolated from biopsies by enzymatic digestion were analysed by multi-colour flow cytometry.

Results

More than 80% of colonic αβT cells were Trm, as defined by CD69 expression, in health and IBD; there was no significant increase in cells with a non-resident phenotype in inflamed tissue. Few CD4+ Trm co-expressed CD103. In contrast, CD8+ Trm comprised CD103+ and CD103- subsets, and CD69+CD103- cells were significantly reduced in IBD. Increased staining for KLRG1 and the cytotoxicity-associated protein perforin, indicated a more effector-like Trm phenotype in IBD. Putative gut-derived ex-Trm were identified amongst TCRαβ+CD45RA- blood cells as a β7++CD103+ population, indicative of cells expressing both α4β7 and CD103(αE)β7 integrin complexes.  A separate CD103β7+α4β7 population defined by 1:1 expression of CD103 and β7 contained CLA+ skin ex-Trm. Gut ex-Trm comprised 0.3% of circulating CD8T cells (range 0.02-1.4%), and 1.2% of CD4+ T cells (range 0.3-3%). Gut and skin ex-Trm were phenotypically similar; both expressed the residency associated markers CD9 and CD101 but lacked CD69 expression. Gut ex-Trm were phenotypically distinct from both the traditional gut-trophic population (α4β7+CD103-CD45RA) and from naïve T cells. The proportion of gut ex-Trm did not differ between health and IBD. However, gut-derived ex-Trm were significantly reduced, relative to skin-derived ex-Trm, in Crohn’s disease, but not ulcerative colitis, when compared with health.

Conclusion

A putative gut-derived ex-Trm population can be identified in both healthy and IBD peripheral blood, with IBD-associated changes identified in this population and intestinal Trm. Circulating ex-Trm could link discreet areas of intestinal inflammation in Crohn’s disease and there is a selective loss of the gut ex-Trm population from the blood of these patients. The role of ex-Trm in IBD merits further study.

Impact of corticosteroid usage on efficacy and safety outcomes in patients receiving upadacitinib for Ulcerative ColitisECCO'22 Virtual
Year: 2022
Authors: Timothy Raine
Background

The oral, selective Janus kinase inhibitor upadacitinib (UPA) has demonstrated efficacy as induction and maintenance therapy in patients with moderately to severely active Ulcerative Colitis (UC) in a Phase 3 clinical programme comprising two identical induction trials (U-ACHIEVE Induction [NCT02819635] and U-ACCOMPLISH [NCT03653026]) and a maintenance study (U-ACHIEVE Maintenance). This analysis assessed the impact of baseline corticosteroid (CS) use on the efficacy and safety of UPA in patients in these trials.

Methods

Patients were randomised 2:1 to UPA 45 mg once daily (QD) or placebo (PBO) for 8 weeks. Patients who achieved a clinical response at Week 8 were re-randomised 1:1:1 to UPA 15 mg QD, UPA 30 mg QD or PBO for 52 weeks. Here, we report induction and maintenance endpoints and safety data stratified by baseline CS use.

Results

Baseline demographics and disease characteristics were generally well balanced across treatment groups, regardless of baseline CS use. Clinical remission rates among patients receiving UPA 45 mg induction therapy did not differ by baseline CS use (Figure 1A). In the induction period, rates of treatment-emergent adverse events of special interest (AESI), including serious and opportunistic infections, were increased in the UPA 45 mg plus baseline CS group compared with the PBO and UPA without baseline CS groups (Table 1). In the maintenance study, CS tapering was mandated. CS-free remission at Week 52 (defined as clinical remission, per Adapted Mayo Score, and CS free for ≥90 days immediately prior to Week 52) was significantly increased with UPA 30 and 15 mg compared with PBO (both p<0.001; Figure 1B). Among patients receiving UPA maintenance, rates of treatment-emergent AESIs in the baseline CS versus no baseline CS groups were 33% versus 39% and 27% versus 35% in the UPA 30 mg and UPA 15 mg groups, respectively. Malignancy, major adverse cardiovascular events, venous thromboembolic events, and serious and opportunistic infections were reported infrequently in patients receiving UPA (Table 1).



Table 1

Conclusion

This post hoc analysis suggests that, in patients with moderately to severely active UC, UPA is superior to PBO in conferring CS-free remission. Baseline CS use was not associated with any apparent efficacy benefit and carried a potential increased safety risk. These results suggest that achieving early disease control with UPA and without CS use is an optimal treatment strategy for this population.

Impact of COVID-19 on clinical research in IBD8th ClinCom Workshop
Year: 2022
Authors: Timothy Raine
Summary content

Educational objectives:
To discuss impact of COVID-19 pandemic on research activity for commercial and non-commercial studies in IBD
To consider lessons learned regarding efficient trial design
To propose future mitigation in event of further pandemic waves 

Impact of EIMs on drug choiceECCO'22 Virtual
Year: 2022
Authors: Péter Laszlo Lakatos
Summary content
  1.  to understand the prevalence and major types of EIMs in IBD
  2. to understand the impact of EIMs on the disease course and relationship with disease activity in IBD
  3. to review the management and therapeutic choices of EIMs in IBD
  4. to summarize the evidence on specific drug classes in the treatment of IBD with EIMs (e.g. conventional therapies, steroids, anti-TNFs and new biological classes)
  5. to review how the presence of EIMs may modify therapeutic decisions
In-depth characterisation of the serum antibody epitope repertoire in Inflammatory Bowel Disease by high-throughput phage-displayed immunoprecipitation sequencingECCO'22 Virtual
Year: 2022
Authors: Arno Bourgonje
Background

Patients with IBD show distinct antibody responses, particularly against microbiota. However, a comprehensive overview of the antibody epitope repertoire in IBD is lacking. Here, we characterized serum antibody responses in patients with IBD and population controls using a high-throughput phage-displayed immunoprecipitation sequencing (PhIP-seq) workflow and associated these to disease phenotypes and the faecal microbiome.

Methods

PhIP-seq was leveraged to characterise antibody responses against 344,000 rationally selected peptide antigens in 497 patients with IBD which were compared with 1,326 individuals from a population-based cohort (Fig. 1A-B). Antibody profiles were linked to 23 IBD-specific clinical features such as disease location and surgical history and to faecal microbiota composition (Fig. 1C).

Results

Patients with IBD demonstrated distinct antibody epitope repertoires compared with individuals from the general population, with 373 differentially abundant antibody-bound peptides (202 overrepresented, 171 underrepresented) belonging to bacterial flagellins (69), virulence factors (102), other antigens of both commensal and pathogenic bacteria (90) as well as viruses (67) and food proteins (24) (Figure 2). In particular, antibody responses against bacterial flagellins, many of which belong to Lachnospiraceae bacteria (e.g. Roseburia spp.), but also Eubacterium spp. and pathogens (e.g. Legionella, Clostridium, Burkholderia) dominated in patients with Crohn's disease (CD), and were associated with ileal disease involvement and more complicated disease behaviour (e.g. fibrostenotic disease, surgical history) as well as anti-Saccharomyces cerevisiae antibody positivity. Furthermore, many other antigens were newly identified, e.g. decreased responses to E. coli virulence factors and genome polyproteins of enteroviruses, and increased responses to food antigens (wheat, barley) and autoantigens (particularly collagen type I and VI). Antibody epitope repertoires were able to accurately discriminate CD from population controls (area under the curve [AUC]=0.88, test set evaluation), showing very high discriminative performance (positive and negative predictive value of 72% and 93%, respectively, representing predicted classes in test set) (Fig. 3A-C), which was less accurate for ulcerative colitis (UC) (Fig. 3D-F).


Conclusion

This study demonstrates the size, diversity and complexity of systemic antibody epitope repertoires in patients with IBD compared to controls, showing that distinct clinical phenotypes of IBD are characterized by unique antibody signatures. PhIP-seq is a powerful tool for identifying systemic immune-based biomarkers and exposing novel immunological targets in immune-mediated inflammatory diseases like IBD.

In-depth characterisation of the serum antibody epitope repertoire in Inflammatory Bowel Disease by high-throughput phage-displayed immunoprecipitation sequencing8th Y-ECCO Basic Science Workshop
Year: 2022
Authors: Arno Bourgonje
Background

Patients with IBD show distinct antibody responses, particularly against microbiota. However, a comprehensive overview of the antibody epitope repertoire in IBD is lacking. Here, we characterized serum antibody responses in patients with IBD and population controls using a high-throughput phage-displayed immunoprecipitation sequencing (PhIP-seq) workflow and associated these to disease phenotypes and the faecal microbiome.

Methods

PhIP-seq was leveraged to characterise antibody responses against 344,000 rationally selected peptide antigens in 497 patients with IBD which were compared with 1,326 individuals from a population-based cohort (Fig. 1A-B). Antibody profiles were linked to 23 IBD-specific clinical features such as disease location and surgical history and to faecal microbiota composition (Fig. 1C).

Results

Patients with IBD demonstrated distinct antibody epitope repertoires compared with individuals from the general population, with 373 differentially abundant antibody-bound peptides (202 overrepresented, 171 underrepresented) belonging to bacterial flagellins (69), virulence factors (102), other antigens of both commensal and pathogenic bacteria (90) as well as viruses (67) and food proteins (24) (Figure 2). In particular, antibody responses against bacterial flagellins, many of which belong to Lachnospiraceae bacteria (e.g. Roseburia spp.), but also Eubacterium spp. and pathogens (e.g. Legionella, Clostridium, Burkholderia) dominated in patients with Crohn's disease (CD), and were associated with ileal disease involvement and more complicated disease behaviour (e.g. fibrostenotic disease, surgical history) as well as anti-Saccharomyces cerevisiae antibody positivity. Furthermore, many other antigens were newly identified, e.g. decreased responses to E. coli virulence factors and genome polyproteins of enteroviruses, and increased responses to food antigens (wheat, barley) and autoantigens (particularly collagen type I and VI). Antibody epitope repertoires were able to accurately discriminate CD from population controls (area under the curve [AUC]=0.88, test set evaluation), showing very high discriminative performance (positive and negative predictive value of 72% and 93%, respectively, representing predicted classes in test set) (Fig. 3A-C), which was less accurate for ulcerative colitis (UC) (Fig. 3D-F).


Conclusion

This study demonstrates the size, diversity and complexity of systemic antibody epitope repertoires in patients with IBD compared to controls, showing that distinct clinical phenotypes of IBD are characterized by unique antibody signatures. PhIP-seq is a powerful tool for identifying systemic immune-based biomarkers and exposing novel immunological targets in immune-mediated inflammatory diseases like IBD.

Increasing incidence of Inflammatory Bowel Disease in a high prevalence country: A nationwide study in FinlandECCO'22 Virtual
Year: 2022
Authors: Kristi Kontola
Background

The burden of inflammatory bowel disease (IBD) in health care is high and the incidence and prevalence rates of IBD in Finland are among the highest in the world.  Our aim was to assess the actual incidence and the trends of IBD in Finland during 2000-2020 using nationwide registry-based data. We also estimated the nationwide prevalence of IBD in 2000 and  2020.

Methods

This study included patients to whom IBD reimbursement was newly attributed between January 1, 2000 and December 31, 2021. Data were retrieved from the Social Insurance Institution of Finland.  Incidence and prevalence rates were calculated by dividing the number of annual new IBD cases by the size of the population at risk during each calendar year.

Results

A total of 42,498 new IBD cases were identified during years 2000-2020; 31,372 with ulcerative colitis (UC) and 11,126 with Crohn’s disease (CD).The crude annual incidence per 100,000 increases in CD from 7.5 to 13.4 (IRR 1.02, CI 1.019 - 1.025) and in UC from 20.4 to 34.7 (IRR 1.03, CI 1.023 - 1.027) (Fig. 1). The crude prevalence of IBD increases from 376 to 972 per 100,000 (PRR 1.05, CI 1.046-1.047).Men have significantly higher incidence than women in UC (IRR 1.26, CI 1.228-1.284). In contrast, there is no difference between genders among CD patients (IRR 0.98, CI 0.95-1.02). In UC, the peak incidence occurs in the age group 25-29 (Fig. 2), whereas in CD, the incidence is
highest in slightly younger patients (Fig. 3). 

Figure 1. Incidence of ulcerative colitis and Crohn`s disease in Finland  during 2000-2020



Figure 2. Annual incidence of UC by age groups during 2000-2020





Figure 3. Annual incidence of CD by age groups during 2000-2020







Conclusion

During the first two decades of the 21st century, the incidence of UC and CD continues to increase in Finland, and almost one percent of the population has IBD.

Increasing incidence of pouchitis among patients undergoing ileal pouch-anal anastomosis between 1996 and 2018: A population-based Danish cohort studyECCO'22 Virtual
Year: 2022
Authors: Edward Barnes
Background

Current knowledge regarding the epidemiology of pouchitis is based on highly selected, mostly single-center, patient cohorts. Our objective was to prospectively determine the population-based incidence of pouchitis in patients with ulcerative colitis (UC) in the first 2 years after ileal pouch-anal anastomosis (IPAA) and analyze time trends of the incidence of pouchitis.

Methods

We used national registries to establish a population-based cohort of all Danish patients undergoing proctocolectomy with IPAA UC between 1996 and 2018. The primary outcome was the development of pouchitis within the first 2 years after IPAA, evaluated by time period of IPAA. The period of IPAA was categorized as follows: 1996-2000 (pre-biologic-1), 2001-2005 (pre-biologic-2), 2006-2010 (early-anti-TNF), 2011-2014 (expanding anti-TNF), 2015-2018 (current biologic). Pouchitis was defined using a previously developed case-finding definition for use in administrative claims data. Kaplan Meier and Cox Proportional Hazard modeling were utilized in the evaluation of time to development of pouchitis.

Results

We identified 1,664 patients that underwent an IPAA for UC. The cumulative incidence of pouchitis in the 2 years after IPAA increased throughout the study period, from 40% in 1996-2000, (95% CI:35%-46%) to 55% in 2015-2018, (95% CI:48%-63%, Table 1).  Patients undergoing surgery between 2015-2018 also demonstrated an increased risk of pouchitis compared to the earliest study period (1996-2000) after adjusting for sex, age, and socioeconomic status (Hazard Ratio [HR] 1.57, 95% CI:1.20-2.05, Table 2, Figure 1). In a separate model adjusting for the same clinical and demographic factors, there was no significant relationship between the preoperative use of anti-tumor necrosis factor alpha therapy use and the risk of pouchitis when evaluated in the entire population (HR 1.14, 95% CI:0.93-1.40) and when evaluated by time period of surgery. 



Conclusion

This first population-based study demonstrated a 15% absolute and 38% relative increase in the incidence of pouchitis among patients undergoing surgery between 1996 and 2018, with the greatest cumulative incidence of pouchitis demonstrated in the most recent era (2015-2018). The striking increase in the incidence of pouchitis highlights the need for further research into causes and prevention of pouchitis.

Infections with biologics and small molecules: Impact on drug positioningECCO'22 Virtual
Year: 2022
Authors: Pierre Ellul
Summary content

1. Define the various risk factors for serious infection and opportunistic infections
2. To go over the various immunosuppressive medications that are routinely used and review the evidence with regards to risk for infection.
3. To assess the various single medications and risk of infection
4. To assess the risk of infection with dual and triple immunosuppressive therapy
5. Prevention of infection through screening and vaccination

Inflammatory Bowel Disease (IBD) and Solid Organ Transplantation. Natural history of pre-existing and de novo IBD patients. (EITOS study of GETECCU)ECCO'22 Virtual
Year: 2022
Authors: Iria Bastón Rey
Background

Limited data is available of the outcome of inflammatory bowel disease (IBD) in patients with solid organ transplantation (SOT). The aim of our study was to describe the natural history of pre-existing IBD and de novo IBD after SOT.

Methods

A retrospective, observational, multi-centre, nationwide study was designed. IBD patients with SOT were included. We identified two separate cohorts: (1) patients with pre-existing IBD at the time of SOT and (2) patients without IBD at the time of SOT (de novo IBD). The primary outcome was IBD progression, defined by the escalation of medical treatment, surgical therapy for medically refractory IBD or IBD-related hospitalization during follow-up. Risk factors were identified using multivariate Cox proportional hazard analysis.

Results

A total of 177 patients (106 pre-existing IBD and 71 de novo IBD) from 31 centres were included. Baseline characteristics are shown in Table 1. Eighty-six patients with IBD and SOT underwent liver transplantation, while 82 required renal, 4 lung, 3 heart, 1 liver/kidney and 1 pancreas/kidney transplantation.

Pre-existing IBD patients were followed-up over a median of 4.8 years (range 2.6-9.4). At the time of SOT, 61 patients (59.8%) were not under maintenance treatment or were treated with 5-aminosalicylates, 10 (9.8%) were on immunosuppressive therapy and 31 (30.4%) were receiving biological agents, of which 8 were on combo therapy. At the moment of SOT, only 8 patients (7.5%) had moderate IBD activity whereas the remaining patients were in remission. During follow-up 33.7% of patients with pre-existing IBD had disease progression, with a median time between SOT and IBD progression of 2.2 years (range 1.3-4.6). No differences between Crohn´s disease and ulcerative colitis were found (Figure 1).

The median time of follow-up in de novo IBD group was 5.1 years (range 2.1-8.2). In this cohort, 55.9% of patients had disease progression during follow-up (Figure 2), with a median time to flare of 1.9 years (range 0.8-3.9) from diagnosis.

In pre-existing IBD cohort, multivariate Cox-regression analysis identified active IBD at the time of SOT (HR=1.80; 95%CI: 1.14-2.84; p=0.012) and the presence of extraintestinal manifestations (HR=3.10; 95%CI: 1.47-6.54; p=0.003) as predictive factors of IBD progression after SOT.






Conclusion

One third of patients with pre-existing IBD have disease progression, needing medical therapy escalation, surgery or hospitalization after SOT. Active IBD at the time of SOT and the presence of extraintestinal manifestations were identified as risk factors for disease progression. In de novo IBD cohort, about half of patients showed disease progression during follow-up.

Infliximab and ustekinumab clearance during induction predicts post-induction endoscopic outcomes in patients with Crohn’s DiseaseECCO'22 Virtual
Year: 2022
Authors: Zhigang Wang
Background

Monitoring of monoclonal antibody clearance has been hypothesised to be an appealing approach for predicting treatment outcomes in patients with inflammatory bowel diseases. We aimed to investigate the benefits of monitoring infliximab and ustekinumab clearance in patients with Crohn’s disease (CD) based on data from clinical trials.

Methods

Data were obtained from patients with moderate-to-severe CD starting infliximab (n=108)1 or ustekinumab (n=80)2 therapy. Endoscopic remission (CD Endoscopic Index of Severity <3) and endoscopic response (≥50% decrease from baseline in simple endoscopic score for CD) were assessed at week (w)12 and w24 of infliximab and ustekinumab therapy, respectively. A priori prediction (based on covariate data only; at w0) and a posteriori prediction (Bayesian forecasting using measured drug concentrations; during treatment) were performed using previously built population pharmacokinetic models (NONMEM 7.5).3,4 Covariates of fecal calprotectin, albumin, CD activity index, and antibodies towards infliximab (ATIs) were used to estimate infliximab clearance. Albumin and body weight were used to estimate ustekinumab clearance.

Results

Patients achieving endoscopic remission at w12 had significantly lower infliximab clearance and higher infliximab serum concentration at w2 and w6 of treatment (P <0.05, Table 1). Patients achieving endoscopic response at w24 had significantly lower ustekinumab clearance at w4 and w8, as well as a significantly larger reduction in clearance relative to w0 (P <0.05, Table 1). However, ustekinumab serum concentrations at w4 and w8 were similar between patients with and without endoscopic response (P >0.2, Table 1).
Most patients with an early increase in infliximab clearance (16/22; 73%) and ustekinumab clearance (27/29; 93%) did not reach the endoscopic endpoint (P <0.05; Table 2). However, a decrease in clearance was no guarantee for endoscopic remission during infliximab therapy (false predictive rate 46%) and response during ustekinumab therapy (false predictive rate 69%).
The infliximab clearance after start of induction therapy (at w2 and w6) was significantly higher in patients who developed ATIs during induction therapy (Figure 1).

Conclusion

Lower infliximab and ustekinumab clearance (absolute as well as relative to w0) early during induction predict more favourable endoscopic outcomes. In patients treated with ustekinumab, clearance monitoring may better predict endoscopic response at w24 as compared to standard therapeutic drug monitoring.

References
1. D'Haens et al.Gastroenterology 2018
2. Verstockt et al. J Crohns Colitis 2019.
3. Dreesen et al. Br J Clin Pharmacol 2021.
4. Wang et al. Br J Clin Pharmacol 2021.




Initial work up after diagnosis of IBD (Tandem talk)6th Basic ECCO: EduCational COurse for Industry
Year: 2022
Authors: Susanna Jäghult; Charlotte Rose Hedin
Summary content
  1. To understand the key tests and investigations that complete the work up of the presenting symptoms 
  2. To understand the scope of factors that affect IBD patients and which patients need to be educated about 
  3. To learn the principles of a collaborative approach when initiating a treat-to-target treatment strategy 
  4. To recognise the different factors that affect quality of life for an IBD patient and to develop a patient-centred approach to improvement in quality of life. 
Integrated tissue transcriptomic and serum proteomic interrogation reveals biomarkers for endoscopic improvement and histologic remission after JAK3/TEC inhibition with ritlecitinib (PF-06651600) in Ulcerative Colitis (UC) (Phase 2b Vibrato study)ECCO'22 Virtual
Year: 2022
Authors: Mina Hassan-Zahraee
Background

Ritlecitinib (PF-06651600) is an oral Janus kinase 3/TEC inhibitor, demonstrated to be safe, well-tolerated and efficacious in moderate to severe active ulcerative colitis. The aim of this pre-specified biomarker study was to develop serum signatures that could serve as non-invasive indicators of endoscopic improvement and histologic remission after ritlecitinib therapy.

Methods

Colon biopsies and peripheral blood were obtained from participants for biomarker profiling before and after receiving 8-week induction therapy with oral ritlecitinib (20mg,70mg, 200mg, or placebo N=39, 39, 33, 18 respectively) once daily. Responders were defined by endoscopic improvement (Mayo endoscopic sub-score <=1) or histologic remission (Geboes Score ≤ 3.0). RNA from colon biopsy samples were processed using RNA sequencing (Fulgent Therapeutics, CA). Serum proteins were measured using the Olink Explore Inflammation panel (Olink, Proteomics, Sweden). Linear mixed models were used to estimate the change from baseline (CFB) of each protein/gene at Week 8 by treatment and clinical response. Differences between response groups and treatment arms were also analyzed.

Results

Analysis of serum revealed 37 proteins significantly changed at week 8 compared to baseline in responders (FDR < 0.05). Changes in four of these proteins (IL4R, TNFRSF4, SPINK4 and LAIR-1) correlate with both endoscopic improvement and histological remission and were able to separate responders from non-responders AUC (area under the ROC curve) = 0.71 [0.61-0.81] based on endoscopic improvement and AUC = 0.60 [0.48-0.71] based on histological remission). To determine if these 37 proteins reflect tissue inflammation, we evaluated the differential expression of genes encoding these proteins with RNA-seq of inflamed biopsies. Ten genes (CXCL1, FCAR, CKAP4, SPINK4, CXCL17, OSM, CD4, CXCL9, IL17A, GZMB) had significant changes from baseline between responders and non-responders at Week 8 (FDR < 0.1) in either endoscopic improvement or histological remission. Furthermore, these ten genes were significantly increased at baseline between inflamed and non-inflamed colon biopsies.   

Finally, colon biopsy transcription levels of TNFRSF4, SPINK4 and LAIR1 were modulated with marginal significance (P-value < 0.1) in either endoscopic improvement or histological remission at Week 8.  

Conclusion

Serum proteomics revealed a promising signature of endoscopic improvement and histologic remission in UC participants treated with ritlecitinib. Changes in a subset of these serum proteins parallel tissue gene expression and offer insight into a potential non-invasive companion monitoring test to guide clinical management of patients treated with ritlecitinib.

Interactive video presentation 19th ECCO Ultrasound Workshop - Advanced in collaboration with ESGAR
Year: 2022
Authors: Rune Levring Wilkens
Summary content

Video case demonstration with the application of intestinal ultrasound disease activity scoring.