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Functional viral neutralisation responses after SARS-CoV-2 infection in Inflammatory Bowel Disease patients receiving infusion therapies: Report from the ICARUS-IBD ConsortiumECCO'22 Virtual
Year: 2022
Authors: Judith Wellens
Background

Recent data havehighlighted adverse clinical outcomes in IBD patients treated with infliximab/thiopurines (IFX/THIO) upon infection with SARS-CoV-2, as well as attenuated serological responses after infection and vaccination in patients treated with IFX. To provide mechanistic insight, we explored the serological and functional anti-viral response after infection in IBD patients treated with VDZ, IFX or IFX/THIO compared to healthy controls to guide clinical decision-making regarding treatment and vaccination strategies.

Methods

Serum from 640 IBD patients attending routine infusions in Oxford and London in May to December 2020 was screened for anti-SARS-CoV-2 antibody responses by the Abbott assay. Serum from seropositive patients was compared to seropositive health care workers (Table 1). Antibody reactivity to the SARS-CoV-2 wild type strain receptor-binding domain (RBD), full-length spike, and nucleocapsid was assayed by IgG/IgA ELISA over time as well as by IgG high-throughput MSD V-PLEX ELISA at the time of seropositivity. A pseudotyped SARS-CoV-2 virus microneutralization assay was used to detect neutralising antibodies to the wild type, and an ELISA-based inhibition assay to compare differential inhibition of the wild type vs. delta variant SARS-CoV-2 RBD-ACE2 interaction.
Table 1

Results

All IBD patients showed significantly reduced IgG antibody responses compared to healthy controls for all SARS-CoV-2 antigens, using MSD V-PLEX ELISA (Figure 1). The greatest reduction in IgG response by ELISA was observed in individuals treated with IFX/THIO (p=0.00019), whereas IgG response over time declined significantly faster in the IFX treated group (p=0.019). IgA responses were significantly reduced in the IFX/THIO group compared to healthy controls (p=0.009), but not in the IFX or VDZ monotherapy group. The rate of decline in these monotherapy groups was also not significantly different to healthy controls. Functional SARS-CoV-2 neutralisation was significantly lower in all IBD patients compared to healthy controls, with the greatest reduction in patients receiving IFX/THIO (Figure 2A; p=0.00000091). The delta variant inhibition capacity was significantly reduced in 68.1% of IBD patients (30/44, Figure 2B; p=0.0005).

Conclusion

IFX/THIO is associated with significantly lower IgA and IgG responses, and with impaired functional SARS-CoV-2 neutralising antibody capacity, compared to healthy individuals. Whilst IgG and neutralisation responses are reduced in each group of IBD patients, these findings were most pronounced in the combination treatment group. As neutralising antibody responses are associated with protection, this observation may impact on decision-making regarding treatment and vaccination/antiviral strategies.

Functional viral neutralisation responses after SARS-CoV-2 infection in Inflammatory Bowel Disease patients receiving infusion therapies: report from the ICARUS-IBD Consortium.8th Y-ECCO Basic Science Workshop
Year: 2022
Authors: Judith Wellens
Background

Recent data havehighlighted adverse clinical outcomes in IBD patients treated with infliximab/thiopurines (IFX/THIO) upon infection with SARS-CoV-2, as well as attenuated serological responses after infection and vaccination in patients treated with IFX. To provide mechanistic insight, we explored the serological and functional anti-viral response after infection in IBD patients treated with VDZ, IFX or IFX/THIO compared to healthy controls to guide clinical decision-making regarding treatment and vaccination strategies.

Methods

Serum from 640 IBD patients attending routine infusions in Oxford and London in May to December 2020 was screened for anti-SARS-CoV-2 antibody responses by the Abbott assay. Serum from seropositive patients was compared to seropositive health care workers (Table 1). Antibody reactivity to the SARS-CoV-2 wild type strain receptor-binding domain (RBD), full-length spike, and nucleocapsid was assayed by IgG/IgA ELISA over time as well as by IgG high-throughput MSD V-PLEX ELISA at the time of seropositivity. A pseudotyped SARS-CoV-2 virus microneutralization assay was used to detect neutralising antibodies to the wild type, and an ELISA-based inhibition assay to compare differential inhibition of the wild type vs. delta variant SARS-CoV-2 RBD-ACE2 interaction.
Table 1

Results

All IBD patients showed significantly reduced IgG antibody responses compared to healthy controls for all SARS-CoV-2 antigens, using MSD V-PLEX ELISA (Figure 1). The greatest reduction in IgG response by ELISA was observed in individuals treated with IFX/THIO (p=0.00019), whereas IgG response over time declined significantly faster in the IFX treated group (p=0.019). IgA responses were significantly reduced in the IFX/THIO group compared to healthy controls (p=0.009), but not in the IFX or VDZ monotherapy group. The rate of decline in these monotherapy groups was also not significantly different to healthy controls. Functional SARS-CoV-2 neutralisation was significantly lower in all IBD patients compared to healthy controls, with the greatest reduction in patients receiving IFX/THIO (Figure 2A; p=0.00000091). The delta variant inhibition capacity was significantly reduced in 68.1% of IBD patients (30/44, Figure 2B; p=0.0005).

Conclusion

IFX/THIO is associated with significantly lower IgA and IgG responses, and with impaired functional SARS-CoV-2 neutralising antibody capacity, compared to healthy individuals. Whilst IgG and neutralisation responses are reduced in each group of IBD patients, these findings were most pronounced in the combination treatment group. As neutralising antibody responses are associated with protection, this observation may impact on decision-making regarding treatment and vaccination/antiviral strategies.

Gaps in IBD care and research6th Basic ECCO: EduCational COurse for Industry
Year: 2022
Authors: Peter Bossuyt
Summary content

Educational objectives:

1. To understand the research in the missing links in the pathophysiology of IBD
2. To understand the need for increased quality of care in IBD and the impact on long term outcomes
3. To review the need for personalized medicine and the requirement from a research perspective

Getting Published!8th Y-ECCO Basic Science Workshop
Year: 2022
Authors: Laurence Egan
Summary content

In this lecture, I will discuss the essential ingredients to doing excellent research which the prerequisite to getting your work published in the best journals, such as the Journal of Crohn's and Colitis. I will also give an overview of how to pick the right journal and review the processes that editors use to select what to publish.

Educational objectives
1. To learn the essential ingredients for good research
2. To understand how to target your work to the best journal
3. To understand how your paper is evaluated by editors using the peer review process

Hedgehog signalling controls Th17 differentiation to drive intestinal inflammation and is a druggable target for the treatment of IBDECCO'22 Virtual
Year: 2022
Authors: Joachim Hanna
Background

T helper 17 (Th17) cells play an important role in barrier protection in the gastrointestinal tract but are also key pathological drivers of Inflammatory Bowel Disease (IBD). Although a number of transcription factors governing Th17 differentiation have been identified, the intracellular signalling pathways regulating Th17 differentiation are poorly understood. Hedgehog (Hh) signalling controls cell-fate choices in numerous tissue compartments and is targetable by highly selective, clinically-approved small molecule inhibitors. However the role of Hh signalling in Th17 differentiation and effector function is unstudied.

Methods

We generated two conditional knockout mouse models targeting Hh signalling components Smo and Ihh to study Th17 differentiation in vitro by flow cytometry and gene expression analysis. For in vivo studies, T cell adoptive transfer colitis was performed using donor Ihh knockout T cells or heterozygote controls. Histological analysis, mouse weight, colon length/weight measurements, and flow cytometric analysis was performed. We supplement this with the use of two small-molecule Smo antagonists for in vitro and in vivo studies of Th17 function. To underscore the translational relevance of our findings, we conducted bioinformatic analyses of published gene expression datasets of human rectal biopsies from two large independent cohorts of Ulcerative Colitis patients and healthy controls.

Results

We find that intracellular Hh signalling, independently of extracellular Hh ligands, selectively drives differentiation and effector function of Th17 cells but not of other T helper cell lineages. We demonstrate in vivo that inhibition of the Hh pathway with either the clinically-approved small molecule inhibitor vismodegib or genetic ablation of Ihh in CD4T cells results in a significant decrease in histological and clinical readouts of disease severity as well as a significant reduction in IL-17a+ Th17 cells. Our bioinformatic analyses show that Hh component expression levels are upregulated in human Ulcerative Colitis patient samples and are closely correlated with expression of Th17 markers. Mechanistically we show that the T-cell-intrinsic Indian Hedgehog (Ihh) ligand signals via the signal transducer Smoothened to activate both canonical and non-canonical Hh pathways, through the Gli3 transcription factor and AMPK phosphorylation, respectively.

Conclusion

We uncover Hh signalling as a novel pathway controlling Th17 differentiation and pathogenicity in IBD with Gli3 acting as a newly-identified crucial regulatory transcription factor. Our work paves the way for the use of Hh inhibitors for the treatment of IBD.

Histologic disease activity correlates with endoscopic severity in patients with moderate to severe Crohn’s DiseaseECCO'22 Virtual
Year: 2022
Authors: Walter Reinisch
Background

The role of histopathology evaluation in Crohn’s disease (CD) is not precisely defined. Due to the heterogeneity of phenotypes, the discontinuity of distribution, and the transmural nature of inflammation, the interpretation of histologic outcomes is complex. To analyze how histology relates to established outcomes in CD, we examined association between histologic and endoscopic disease activity measured by frequently used scores (simple endoscopic score for Crohn’s disease [SES-CD], Robarts histopathology index [RHI], global histological activity score [GHAS]) and the association between histologic or endoscopic severity with inflammatory biomarkers in a cohort of patients with moderate-to-severe CD.

Methods

Patients (N=191) who were enrolled in a phase 2 randomized clinical trial (NCT02891226) in patients with moderate-to-severe CD were assessed at baseline (BL) for endoscopic disease location and severity as measured by SES-CD. Biopsies were obtained during BL endoscopy from the edge of the ulcers and the most inflamed mucosa in terminal ileum and 4 colonic segments (ascending, transverse, descending, rectum; N=10/patient, 2 per location with the more severe score used), and scored by central readers blind to study treatment, timepoint, and response status using RHI and both modified and active GHAS (mGHAS: Q1, 3, 4, 5, 6; aGHAS: Q1, 4, 5, 6; see Fig. 1). Inflammatory biomarkers included fCLP and CRP; log-transformed values are used. Linear correlations between measures were determined using Pearson correlation coefficients (PCC) as exploratory analyses. Nominal p values are presented.

Results

SES-CD correlated well with all 3 histologic measures examined (Fig. 1). While both fCLP and CRP correlated more closely with endoscopy than with histologic measures, fCLP had higher correlation with each histologic measure than CRP (Fig. 2). 64% of patients had the same disease location at BL when measured by endoscopy or histology. Patients with endoscopic colonic disease displayed histologic ileal involvement in up to 20% of cases, while 13% of patients with endoscopic ileal disease demonstrated histologic colonic involvement (Table 1).

Conclusion

Although histologic disease activity in CD, as determined by 3 different measures, correlates well with endoscopic assessment of disease, histologic involvement provides complementary information on disease distribution and extension. Further analyses are required to understand the additive role of mucosal histology in CD.





Histologic markers of chronicity of IBD7th H-ECCO IBD Masterclass
Year: 2022
Authors: Pamela Baldin
Summary content

Differential  diagnosis of IBD and chronic colitis could be challenging. In this presentation the histological features of chronicity in IBD will be resumed  and differential diagnosis pointed out.

Educational objectives:
- understand the main features of chronicity of IBD
- compare these features with the main differential diagnosis.

Host and microbial metabolites as therapeutic targets in IBD10th SciCom Workshop
Year: 2022
Authors: Konrad Aden
Summary content

. to understand the role of metabolism in IBD
- to identifiy key metabolic principles (SCFA, Bile Acid, Tryptophan)  that have shown to be relevant in the pahtophysiology of IBD

Hot topics in IBD7th H-ECCO IBD Masterclass
Year: 2022
Authors: Gert De Hertogh
Summary content

Educational objectives:
Give an overview of recently published work on IBD / Crohn's disease / ulcerative colitis

Summary
Possible subjects will include:
1) Very early-onset IBD
2) Granulomatous gastritis
3) Appendiceal inflammation in Crohn's disease and in ulcerative colitis
4) An important differential diagnosis of Crohn's disease
5) Precursor lesions of IBD-associated neoplasia and features of Crohn's and colitis-associated bowel cancer
6) Something that may come as a surprise

How important is IBD?2nd ECCO Postgraduate Course in IBD
Year: 2022
Authors: Janneke van der Woude
Summary content

1. To understand the epidemiology of IBD
2. To understand the impact of the disease on quality of life

How the adult's clinic takes care of the young addult16th N-ECCO Network Meeting
Year: 2022
Authors: James Lindsay
Summary content

1) Highlight differences in disease presenting in adolescence compared to adulthood
2) Discuss the concept of transition vs transfer and the risks
3) Review the options available for transition and tools used to measure progress
4) Discuss guidelines

How to conduct the data collection?7th N-ECCO Research Forum
Year: 2022
Authors: Wladyslawa Czuber-Dochan
Summary content

Educational objectives:
1. To understand the different methods of data collection for different study designs e.g qualitative, quantitative, mixed methods
2. To emphasise the role of different types of data collection methods e.g. interview, observation, survey, etc
3. To empasise practical issues to consider when data collecting 

How to diagnose and evaluate a new IBD case?2nd ECCO Postgraduate Course in IBD
Year: 2022
Authors: Laurent Peyrin-Biroulet
How to optimise the old school IBD Meds?2nd ECCO Postgraduate Course in IBD
Year: 2022
Authors: Shomron Ben-Horin
Summary content

 In this talk we will discuss simple yet often overlooked pearls and tips to get the most of old-school medications, focusing on thiopurines and 5ASA. We will examine which combination of topical and oral 5ASA is best in each clinical scenario, discuss the role of compliance, how to optimize technical aspects of rectal agents, desensitization and factors not to be overlooked which may contribute to recalcitrant IBD. We will also explore metabolite testing for thiopurines in clinical practice and the evidence backing its use for maintenance monotherapy 

How to place new biologics and small molecules?2nd ECCO Postgraduate Course in IBD
Year: 2022
Authors: Silvio Danese
How to place surgery in IBD?2nd ECCO Postgraduate Course in IBD
Year: 2022
Authors: Paulo Gustavo Kotze
How to prepare the research question?7th N-ECCO Research Forum
Year: 2022
Authors: Simona Fourie
Summary content

1. To discuss what makes a good research question 
2. To review the process of formulating a research question
3. To understand the researcher factors to be considered when formulating a research question  

Humoral immune response after SARS-CoV-2 vaccination in patients with immune-mediated inflammatory diseases treated with immunosuppressive therapy - a Target to B! studyECCO'22 Virtual
Year: 2022
Authors: Adriaan Volkers
Background

The aim of this study was to investigate the effect of various immunosuppressants on the humoral immune responses after vaccination against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs).

Methods

The Target to B! SARS-CoV-2 study is a multicentre study, taking place in 7 Dutch academic hospitals. Patients with the following IMIDs were recruited: Crohn’s disease (CD), ulcerative colitis (UC), auto-immune hepatitis, rheumatic (e.g. rheumatoid arthritis), neurological (e.g. multiple sclerosis) and dermatological IMIDs (e.g. atopic dermatitis). Patients were recruited based on immunosuppressants (table 1) and previous SARS-CoV-2 infection. The control group consisted of healthy subjects and IMID patients without immunosuppressants. SARS-CoV-2 receptor binding domain (RBD) antibodies were measured 28 days after completed SARS-CoV-2 vaccination. Seroconversion was defined as anti-RBD IgG >4 AU/mL. In this abstract, we focus on therapies relevant for inflammatory bowel diseases (IBD) and present results for these treatments from patients with IBD, but also other IMIDs.

Results

Numbers of recruited patients with each immunosuppressant are shown in table 1. Amongst these patients, 312 patients had CD and 176 UC, the rest was diagnosed with another IMID. Seroconversion was reduced in patients receiving sphingosine 1-phosphate (S1P) modulators (all multiple sclerosis patients) while seroconversion was similar to controls in the other treatment groups. However, use of Anti-tumour necrosis factor (TNF), methotrexate, janus kinase (JAK) inhibitor monotherapy and all combination therapies (except for corticosteroids combined with other immunosuppressants) were associated with reduced Sars-CoV-2 antibody titres. Patients with a previous SARS-CoV-2 infection had higher median antibody titres after second vaccination than those without a previous SARS-CoV-2 infection. The type of IMID did not affect seroconversion rates.

Conclusion

No immunosuppressant, registered for IBD, reduced the rates of seroconversion after vaccination against SARS-CoV-2. Some immunosuppressants were associated with lower antibody titres. However, the clinical relevance of lower antibody titres remains unknown. S1P modulators, had a clear negative impact on the humoral response against SARS-CoV-2 after vaccination. This might be relevant in the future as this therapy is currently being approved for UC. Disease aetiology did not impair immunity against SARS-CoV-2 immunity after vaccination. Disclaimer: Absolute numbers of antibody titres and rates of seroconversion will be reported at the conference and are not reported in this abstract as this might negatively impact the current submission process.

I want to see my patient in person vs. I can manage my patient remotely (Tandem talk)ECCO'22 Virtual
Year: 2022
Authors: Glen Doherty; Remo Panaccione
Summary content

Educational objectives:
To provide insights into the role of telemedicine in remote patient management in IBD
To review the evidence for improved treatment outcomes associated with the use of telemedicine and remote monitoring strategies
Highlight some of the potential limitations and the gaps in evidence that need to be addressed in the future

Educational objectives: 

  1. To review the elements needed to deliver best care to patients with inflammatory bowel disease.
  2. To review the benefits of live patient interaction in the management of inflammatory bowel disease.
  3. To emphasize the future role of hybrid care delivery in inflammatory bowel disease
  4. To discuss best practices in care delivery in the virtual/digital age

In response to the COVID-19 pandemic, many jurisdictions quickly to  virtual care models, defined as any remote, technology-based interaction between a health-care provider and a patient or patient representative. It can be a phone call, videoconference, email exchange or a text. While this tool has been essential in reducing the risk of viral transmission, providing care for patients who need ongoing medical attention may have unintended consequences and if not done properly may lead to poorer health outcomes and this includes in patients with inflammatory bowel disease.

 

While these tools have advantages for certain patient care needs, including providing necessary virtual pathways to care in remote and Indigenous communities, the pandemic experience has also reinforced the vital importance of hands-on in-person care. There are limits to what can be done virtually and the standard of care is often difficult to meet in a virtual care environment.

 

There are advantages of virtual care, including improving access to care, especially for patients who cannot easily travel to a clinic; simplifying the coordination of care for; saving patients travel time and the cost of missing work or making caregiving arrangements.  In inflammatory bowel disease, disease monitoring has also been facilitated by the widespread use of apps and fecal calprotectin.  However, given the complexity of patients with inflammatory bowel disease there continues a need to see these patients in person to establish and re-enforce the doctor-patient relationship, ensure proper examination and rule out complications and provide the necessary psychosocial support that virtual care cannot meet.

 

In the future, lessons learned from the necessity of transitioning to virtual care during the pandemic will certainly find themselves into new hybrid care models which employ a mix of in-person evaluation and efficient, secure and meaningful, and effective virtual care.

IBD and cancer - Medical or surgical therapy?11th S-ECCO IBD Masterclass
Year: 2022
Authors: Manasi Agrawal
Summary content

Educational Objectives:

1. To review the epidemiology of cancer in IBD
2. To understand the impact of IBD medications on incident and recurrent cancer, as well as impact on active cancer
3. To understand the impact of cancer therapies on IBD outcomes
4. To review therapeutic strategies for IBD in individuals with cancer