Exabis Library

Learning Objectives:
1. Aspects of risk stratification
2. Utility of drugs that may alter the natural history (reducing rates of surgeries and complications)
3. Timing of intervention
4. Evidence base data  comparing different classes
5. Economic consideration/medical economics including the utility of biosimilars

Several potential risk factors for disease recurrence after surgery have been identified, includingage, disease phenotype, and smoking. In the light of the evolution of prevention and management ofpostoperative recurrence, including early immunosuppressive and biologic treatments, theidentification of potential risk factors is pivotal. Despite the clinical significance, few studies haveinvestigated the association between postoperative complications and recurrence in Crohn’s disease(CD) patients after primary ileocolonic resection. A retrospective analysis of consecutive patientsundergoing primary ileocolonic resection for CD at two European referral centers was performed toaddress the effect of postoperative complications on endoscopic and clinical recurrence. Data from262 patients were retrieved from the Institutional databases: 145 patients developed endoscopicrecurrence and 117 patients were recurrence-free. At multivariable analysis, smoking, penetratingphenotype, perianal disease, and postoperative complications were risk factors for endoscopicrecurrence. Postoperative complications and penetrating disease significantly reduce the time toendoscopic recurrence; postoperative complications and penetrating disease significantly shortenthe time to clinical recurrence. In summary, postoperative complications rate was an independentrisk factor for endoscopic recurrence after primary surgery for CD and affected the rate and timingof endoscopic and clinical disease recurrence.

Crohn’s disease is a chronic progressive inflammatory disease of the gastro-intestinal tract that may lead to bowel damage and disability. Half of patients will require surgery within ten years of diagnosis. Unfortunately, surgery is not curative, endoscopic recurrence is reported in 80% of patients within one year of diagnosis, and predicts clinical and surgical recurrence. The prevention of post-surgical recurrence is a critical target in the care of Crohn’s disease after surgery. Currently, postsurgical management and treatment of Crohn’s disease are based on endoscopic monitoring performed during the first year after surgery. However, colonoscopy is an invasive and expensive procedure, unpleasant to patients. Bowel ultrasound is a cheap, non-invasive, readily-available tool for the assessment and the monitoring of patients with inflammatory bowel disease, especially patients with Crohn’s disease. This presentation aims to review the evidence for the use of bowel ultrasound in the specific setting of postsurgical recurrence in Crohn’s disease; the diagnostic accuracy of bowel ultrasound in the detection of postsurgical recurrence in alternative to colonoscopy; its predictive value for clinical and surgical recurrence.

Jérémie Lefevre discusses the work of the GETAID surgical group examining post-operative outcomes for a large series of patients undergoing repeat ileocolonic resection and reports some reassuring findings.

The current novel coronavirus (SARS-CoV-2) pandemic is an ongoing global health crisis, which represents an important challenge for the whole society and mankind. Patients with inflammatory bowel disease (IBD) are treated with immunosuppressive drugs that are usually associated with more severe viral infections. However, the effects of the different therapies on the risk of SARS-CoV-2 infection and Covid-19 severity in IBD patients are still under investigation.

Between April 2020 and April 2021, 238 IBD patients (N=145 with Crohn disease and N=93 with Ulcerative colitis) of the North Italy area have been enrolled. Both serum samples (N=238 IBD patients and N=45 healthy donors) and colon biopsies from inflamed and non-inflamed mucosa (N=88 IBD patients N=20 non-IBD control) have been collected. To evaluate the exposure to SARS-CoV-2, both clinical data and seroprevalence of anti-SARS-CoV-2 Ab have been analyzed. Serum samples were analyzed by untargeted metabolomics analysis and the frequency of a serum metabolomics signature associated with protection were evaluated in IBD versus healthy donors. Moreover, gene expression analysis of key proteins for virus entry (ACE2, TMPRSS2, TMPRSS4, ADAM17) were analyzed by qPCR in the gut mucosa biopsies of IBD patients.

The seroprevalence of anti-SARS-CoV-2 Ab in our cohort of IBD patients (10/238) indicates an overall lower incidence of COVID-19 in comparison with the general population of Lombardy. Accordingly, we observed that the serum metabolomics signature associated with protection was more frequent in IBD patients treated with anti-TNF (N=50, 70%), than healthy controls (N=45, 50%). Gene expression analysis of the proteins involved in SARS-CoV-2 entry also indicated that IBD patients treated with anti-TNF (N=14) had a lower mucosal level of SARS-CoV-2 receptor ACE2 and its sheddase ADAM17 than non-IBD subjects along with higher expression of the proteases TMPRSS2 and TMPRSS4.  Moreover, vedolizumab-treated patients (N=7) showed a significant lower expression of ACE2, TMPRSS2 and TMPRSS4 than controls, whereas ADAM17 levels were similar.

Our study indicates that IBD population treated with biologics has an overall lower risk to contract SARS-CoV-2 infection. Future studies to gather the mechanisms underpinning the effects of biologics on the expression of the proteins involved in SARS-CoV-2 viral entry in association with the specific metabolomics signature of viral susceptibility might shed light on potential targets to increase resistance in higher risk subgroups of patients.

The ileal pouch-anal anastomosis (IPAA) is the gold standard to restore intestinal continuity inpatients with ulcerative colitis (UC), familial adenomatous polyposis (FAP), and in selected patientswith Crohn’s disease (CD) undergoing proctocolectomy. IPAA produces reasonable long termresults and is associated with low mortality as well as good patient satisfaction. However, long-term pouch failure may occurs in a minority of cases. Various IPAA-related complications such asanastomotic leakage, pelvic sepsis, fistula, stricture, pouchitis and “crouchitis” are associatedwith pouch failure. Pelvic sepsis is reported to be the most important risk factor for pouch failure.The rate of IPAA-related complications varies widely in the literature and may have increased inthe era of biologics. However, ambiguous definitions for anastomotic complications, differences inpostoperative assessment, and duration of follow-up make a comparison of outcomes followingIPAA challenging. Although re-do pouch surgery is feasible it has been generally associated withworse outcome when compared to primary surgery. For this reason pouch surgery has the right tobe considered as a “once in a life time surgery”. To reduce the risk of pelvic sepsis, the focus hasbeen on optimization of preoperative performance status, staged procedures, fecal diversion, andadequate postoperative management (ie, early detection and pro-active treatment of anastomoticleaks). From a technical point of view, since its introduction in 1978, restorative proctocolectomyhas gone through a progressive evolution including the application of stapled anastomosis,minimally invasive approach and transanal technique. Transanal techniques and single stapledanastomosis have the potential to standardize the length and shape of the rectal cuff and thereliability of the anastomosis respectively with subsequent impact of long term outcomes in termsof function.

To provide an overview of expanding treatment options in IBD
To provide expert opinion of how to navigate through the different therapeutic options in IBD

Educational objectives:
1. To review IBD-associated alterations in microbial composition and metabolite production, which contribute to regulation of intestinal inflammation
2. To discuss how these microbiome alterations may serve as future therapeutic targets for precision intervention

The management of inflammatory bowel disease (IBD) requires a personalized approach to manage a heterogeneous group of patients with variable disease courses. Precision care in IBD involves identifying patients at high risk for rapid progression to complications, selecting the most appropriate therapy for a given patient, predicting response to therapy and safety of drugs. Personalized medical decisions may allow specific therapeutic plans to draw on serologic, genetic, and microbial data to optimise treatment outcome.

The HLA-DQ polymorphism is likely to become important for patient stratification. Over 30% of patients with IBD have this polymorphism. Variants in the HLA-DQA1*05 allele are associated with greater likelihood of immunogenicity and this risk can be greatly reduced by use of a concomitant immunomodulator. Patients with high levels of a blood cytokine level, Oncostatin M, are also less likely to respond to anti‑TNF. Integrating multi-omics including faecal metagenomic, serum metabolomic and proteomic profiles can predict differential response to anti-cytokine or anti-integrin therapy. In predicting treatment safety, leukopenia-free survival is improved when genotyping for NUDT15 prior to therapy initiation with subsequent genotype-based dosing in a Japanese cohort.

Patients with a more diverse baseline microbiome and higher microbial diversity showed better response to anti-TNF agents, vedolizumab, and ustekinumab. Fewer mucus-colonising bacteria, a higher abundance of short-chain fatty acid-producing bacteria, and lower abundance of pro-inflammatory bacteria are also associated with a favourable outcome. The microbiome may also play a role in determining which patients can stop treatment once they are in deep remission. In the future, the combination of metabolomic, metataxonomic, or metagenomic profiling can further enhance precision medicine in IBD.

1. Overview about Precision medicine
2. Strategies to prevent disease complications: what is in the clinic already?
3. Data on precision medicine in IBD patienst aiming to prevent disease complications

Monitoring has become an essential component of up-to-date IBD patient care. Calprotectin and imaging (ultrasound, endoscopy, MRI) will be discussed as precision monitoring tools with their advantages and disadvantages. A practical algorithm for precision monitoring will be suggested.

The insufficient effects of current medical IBD therapies have led to the contention that therapeutic approaches can be improved by personalizing care using precision medicine.  This process entails an effort to combine clinical patient characteristics and mechanistic drug effects and align them with therapeutic outcomes, thereby providing biomarkers for selecting the appropriate drug for individual patients. Significant challenges for identification of response biomarkers include patient heterogeneity and the complexity of drug response mechanisms.

An analytic approach based on molecular correlation networks may allow to perturbate this complexity and provide necessary insights to employ this strategy.
We used the comparison of disease versus healthy immune landscape and immune system dynamics during therapy, combined with assessment of individual immune responses to approach this complex landscape.

Using this approach, we identified peripheral blood baseline expression of the cytoskeleton RAC/PAC pathway as a response biomarker for infliximab therapy, both in Crohn’s disease and Rheumatoid arthritis patients, thus identifying a patient-specific rather than disease-specific biomarker.
Notably, this pathway was also associated with the TREM adaptor (TYROBP/DAP12) downstream to TREM-1, which we previously found to be predictive for anti-TNF response. When tested in a control cohort of vedolizumab responsive patients, this biomarker was found to be infliximab-specific and responsive to therapy. Pathway expression was predominantly driven by intermediate monocytes.

Furthermore, identification of the RAC/PAC pathway as central to infliximab response, provides an additional potential mechanistic explanation for the documented synergistic effects of anti-TNF thiopurines combination, translating the findings into clinically relevant established observations.
Leveraging this approach may also allow for future discovery of other effective drug combinations and novel therapeutic compounds.