Exabis Library

Educational objectives:
1. To understand the mechanism of action of Methotrexate
2. To review its efficacy and appropriate use (mono-, combitherapy)
3. To learn the appropriate management of Methotrexate and its potential adverse events in daily practice
4. To have an overview on other alternative indications

Educational objectives:
1) To demonstrate that IBD shares many endoscopic and histological features with other diseases.
2) To emphasize that the pathologist needs sufficient and qualitative clinical information to arrive at a correct diagnosis

Summary
Chronic inflammatory bowel diseases (IBD) are especially prevalent in Europe and North America. Their etiology and pathogenesis remain largely unknown.
IBD is diagnosed by a specialists' team consisting of gastro-enterologists, radiologists, surgeons, endoscopists, and pathologists.
The gastro-intestinal tract has however a limited number of responses to injury, therefore some conditions may simulate IBD clinically and histologically.
The mimickers of IBD fall in 4 groups:
1) Infections (particularly bacterial, but also viral, parasitic and fungal)
2) Specific and localized inflammations (e.g. diverticular colitis, endometriosis)
3) iatrogenic (including mainly drugs and medical interventions)
4) Other rare medical causes of IBD-like changes.  

We have previously shown that treatment with mirikizumab (miri), a p19-directed IL-23 antibody, significantly downregulates inflammatory genes associated with disease activity and upregulates genes expressing epithelial transporter proteins in colonic tissue in patients with ulcerative colitis (UC). Here we explored the correlation between the expression of colonic mucosa genes and stool frequency (SF), a symptom reflective of disease activity, during the 12-week induction period of a Phase 2 study of patients with moderately to severely active UC (NCT02589665).

Patients were randomised 1:1:1:1 to receive intravenous placebo (PBO), miri 50mg or 200mg with possibility of exposure-based dose increases, or fixed miri 600mg every 4 weeks for 12 weeks. SF was reported daily by patients and transformed on a 4-level ordinal scale [0-3] representing increased SF above their normal or healthy baseline (BL). Patient colonic biopsies (PBO N=58, miri 50mg N=52, 200mg N=51, 600mg N=54) were collected at BL and Week (W)12, and gene expression measured using an Affymetrix HTA2.0 microarray workflow. BL and W12 gene expression or SF values were pooled and associations identified based on non-parametric Kendall’s tau. Pathway analysis (Hallmark and Reactome) of correlated genes was performed using over-representation analysis. p values of enrichment were determined by hypergeometric distribution test and adjusted for multi-testing with Benjamini-Hochberg procedure. Differential gene expression after miri treatment was determined by paired t-test comparing expression levels at BL and at W12 using data from the 200mg treatment group.

A total of 267 genes were correlated with SF (|tau| >0.3 and qval <0.001).  Of these, 212 were positively correlated (high expression associated with high SF) and 55 were negatively correlated (high expression associated with low SF). The 212 transcripts that were positively correlated with SF were uniformly and consistently downregulated with miri treatment, while the 55 transcripts that negatively correlated with SF, were consistently upregulated with miri treatment (Table 1). Biological pathways significantly associated with the miri-responsive transcripts that correlated with SF included inflammatory response, extracellular matrix dysregulation, neutrophil degranulation and cytokine signaling pathways, especially TNF and IL6 pathways (Table 2).

This is the first study to identify colon-based transcripts that correlate with a clinical disease activity measure, stool frequency, and it demonstrates that treatment with miri may upregulate genes associated with normalization of SF and down regulate genes associated with inflammation in colonic tissue samples of patients with UC.

Educational objectives:
1. To provide an overview of different models of IBD.
2. To discuss the choice and appropriateness of different IBD models for different research questions.

To understand the effect of various groups of IBD medications on histology and review the evidence of histological healing 
To review some practical points in relation to microscopic assessment of post surgical changes in diverted rectum & ileo-anal pouch histology

Long-term outcomes data after modified 2-stage ileal pouch anal anastomosis (IPAA), defined as completion proctectomy (CP) and IPAA without loop ileostomy, is lacking. We aimed to describe long-term functional results, patient satisfaction, and pouch survival in a cohort of patients from a high-volume center. We hypothesized selective m2-stage can result in comparable long-term pouch survival relative to a 3-stage approach.

Our institutional ileal pouch database was retrospectively reviewed to identify patients who underwent index IPAA surgery from 1983–2019. Adults >18 years of age who underwent CP with IPAA were included. At our specialized institution, m2-stage is performed selectively based on surgeon judgement. Patients were stratified into 2 groups (3-stage vs m2-stage) and matched on a 1:1 basis based on age ±5, year of operation ±3, gender, preoperative diagnosis, double-stapled vs handsewn, and laparoscopy. Primary outcome was pouch survival, with pouch failure defined as permanent diversion, pouch excision, or conversion to a Kock pouch.

In total, 2,433 patients were included, of whom 2,198 (90.3%) underwent 3-stage IPAA and 235 (9.7%) m2-stage IPAA. Matching resulted in 223 matched pairs, and long-term pouch survival (95.5% vs 93.2%, p=0.32) did not significantly differ (Figure 1). Short-term outcomes in the matched pairs revealed a shorter postoperative length of stay in the 3-stage patients (5 vs 8 days, p<0.001), but no significant difference in postoperative complications (12.1% vs 17%, p=0.09) was seen between the matched 3-stage and m2-stage patients, respectively. Functionally, there was no difference in the number of stools/24 hours (7 vs 7, p=0.33) or in proportion of patients requiring seepage protection at night (29.7% vs 24.6%, p=0.31). However, 3-stage patients required significantly more seepage protection during the day (25.1% vs 15.0%, p=0.02). Regarding pouchitis, there was no difference in the proportion of patients reporting recent symptoms (33.4% vs 33.3%, p=1.0), episodes in the last year (0 vs 0, p=0.51), or pouchitis requiring continuous medication (16.7% vs 10.1%, p=0.10). Patient satisfaction was similar as no difference in the proportion of those who would have surgery again (90.4% vs 93.7%, p=0.34), those who would recommend surgery (94% vs 95.5%, p=0.68), or overall patient satisfaction with surgery on a scale of 1 – 10 (highest) (3 vs 7, p=0.07) was reported.

Figure 1: Kaplan-Meier curve for pouch survival (matched pairs)

Long-term outcomes were similar in patients who underwent modified 2-stage and 3-stage IPAA. Modified 2-stage IPAA is an alternative for selected patients with limited options if performed at high-volume centers in experienced hands.

Summary of the talk

Timely limitation of the inflammatory process is essential, because its self-perpetuation will otherwise lead to the onset of complications and disease progression. In contrast to inflammatory processes, resolution of inflammation and molecular healing are far less well understood in IBD. In-depth characterization of pathways that terminate inflammation and lead to molecular healing has been incomplete to date. Resolution of inflammation involves several active processes rather than just a stepwise clearance of pro-inflammatory mediators. Recent studies have shown that blockade of just one of the pro-inflammatory mediators might be circumvented by the activation of alternative, redundant pro-inflammatory pathways, thus leading to loss of response. An improved understanding of these resistance mechanisms would help us to improve our currently used therapeutic strategies and reveal new treatment targets and concepts. Our future therapeutic aim should be the restoration of mucosal homeostasis and resolution of all perturbed molecular components (e.g. activation of immune cells, perturbed epithelial barrier integrity and disturbed antigen tolerance). This kind of molecular healing might minimize the risk for relapses and lead to lasting control of the disease.

1.)    To understand mechanisms that are involved in the resolution of inflammation and molecular healing in IBD

2.)    To get an overview on identified molecular resistance mechanisms to biological therapies and how they could be therapeutically utilized

3.)    To understand how molecular healing could be defined in IBD

Dr Alka Potdar and Dr Janine Bilsborough discuss their paper analysing genetic and transcriptomic sub-classifiers of small bowel Crohn’s and the associated phenotypic characteristics.

https://academic.oup.com/ecco-jcc/pages/podcast 

Some genetic polymorphisms (present in less than 30% of patients) and environmental factors, such as tobacco exposure, have been identified to increase the susceptibility for developing inflammatory bowel disease (IBD), but it is suspected that there may be other still unknown environmental or epidemiological factors. In this sense, some studies suggested an increased incidence of IBD in individuals undergoing bariatric surgery (BS) for morbid obesity (MO). We aimed to assess whether BS or MO are associated with an increased risk of developing IBD.

All individuals resident in Catalonia (7.7 million inhabitants in 2021) with a diagnosis of obesity or MO within the period 2005-2020 were identified from the Catalan Public Health System Database. Children under the age of 18 and those diagnosed with IBD prior to the diagnosis of obesity or MO were excluded. Individuals BS and those with a new diagnosis of IBD were identified, and the likelihood of developing IBD was analyzed by Kaplan-Meier survival analysis. A Cox regression multivariable analysis was performed to assess independent risk factors for the development of IBD, Crohn’s disease (CD) and ulcerative colitis (UC).

Three cohorts were identified: 94,473 individuals with MO; 1,009,256 with obesity; and 14,698 who underwent BS during the study period. A total of 4,277 new diagnoses of IBD were identified, of which 78 among individuals who underwent BS prior to IBD diagnosis (0.84 cases per 1000 person-years), 409 among individuals with OM but without BS (0.90 cases per 1000 person-years), and 3,790 in obese individuals (0.60 cases per 1000 person-years). The likelihood of developing IBD was significantly higher in patients with MO as compared with obese patients (HR 1.46; 95%CI 1.32-1.62). These differences were maintained when the likelihood of developing CD or UC were assessed separately. In the multivariable logistic regression analysis, MO (HR 1,68; CI95% 1.41-1.99), female gender (HR 1.17; 95%CI 1.05-1.31) and active smoking (HR 1.62; 95%CI 1.43-1.84) were associated with an increased risk of CD. In UC, MO (HR 1,36; 95%CI 1.19-1.55) and BS (HR 2.62; 95%CI 1.34-2.11) were independent risk factors, whereas female gender (HR 0.86; 95%CI 0.79-0.93) was an independent protective factor.

MO is an independent risk factor for the development of IBD, for both CD and UC, whereas BS seems to increase the risk only for UC.