Exabis Library

1. To understand the therapeutic gap for which predictive biomarkers are needed. 
2. To review the current state-of-the art in IBD predictive precision medicine
3. To emphasise the main challenges in biomarker development 
4. To prioritise the key areas for research in biomarker development

A major challenge of future IBD patient care is the definition of actionable disease subphenotypes, e.g. to reliably predict disease progression and to provide a rationale for individual therapy selection. Although advances have been made in the description of genetic risk factors and formal pathophysiology (e.g. the description of inflammatory signal transduction), the diagnostic application of non-standard molecular markers in this setting is rather limited. Many studies have focused on investigating pre-selected sets of cellular or transcriptomic signatures at a single timepoint and thereby do not exploit the dynamic molecular changes that may explain individual disease trajectories.Thus, there is an urgent need for improved longitudinal biomarkers and clinical trial designs, which aim to translate such biomarker sets into actual clinical care . Future long-term strategies will likely include diagnostic features from different molecular ( i.e. omics-) layers. I will review selected pivotal molecular studies and aim to delineate promising clinical questions, which could be solved by collaborative efforts across Europe.   

1. To understand why predicting disease course is important
2. To understand the limitations of existing methods for doing this.
3. To recognise the importance of validating the predictive performance of potential biomarkers
4. To understand methods that are currently being investigated for biomarker development
5. To highlight the first biomarker-stratified trial in IBD (PROFILE) that will determine whether personalised therapy is deliverable from diagnosis

Dr John Nik Ding reports his study of urine, faecal and serum metabonomic and microbial predictors of response to anti-TNF therapy in 76 Crohn’s patients.

Learning Objectives:
1. Pre conception counseling, optimal disease control, planning, adherence
2. Drug safety at conception and during pregnancy
3. Management of disease exacerbation during pregnancy, assessment and therapeutic options
4. Management of biologics during pregnancy and post-partum
5. Multidisciplinary decision concerning through the entire pregnancy and important decision like mode of delivery

Alison de Lima and Janneke van der Woude discuss their article summarising the available evidence on the management of pregnancy in IBD in the context of the COVID-19 pandemic.

Primary Sclerosing Cholangitis (PSC) is a chronic and progressive cholestatic disease, characterised by inflammation of the intrahepatic and/or extrahepatic bile ducts, progressive fibrosis and scarring of the liver parenchyma and eventually end-stage liver disease. About 70% of patients with PSC have underlying IBD, most frequently ulcerative colitis (UC). Conversely, in patients with known IBD, PSC is found much less commonly, occurring in about 2% to 8% of UC patients and 3% of Crohn’s disease (CD). Despite initial enthusiasm for a genetic link in PSC-IBD, recent genomics data did not show a strong association. Inflammatory bowel disease coexisting with PSC has a specific behaviour and it is considered a distinct phenotype known as “PSC-IBD”. Prolonged duration of IBD is associated with an increased risk of cholangiocarcinoma (CCA) in PSC patients.
-To have an overview on histological features of PSC.
-To understand the association between PSC and IBD.
-To understand the association between PSC and Cholangiocarcinoma.
-To learn features of cholangiocarcinoma.

Summary: Therapeutic drug monitoring (TDM) has emerged as a useful tool for optimizing biological therapy, and particularly anti-tumor necrosis factor (anti-TNF) therapy, in patients with inflammatory bowel disease (IBD). Growing evidence suggest that proactive TDM of anti-TNF therapy, with the goal of targeting a predefined drug concentration threshold, is associated with better therapeutic outcomes compared to standard of care. Proactive TDM can also be utilized when infliximab de-escalation is considered and following infliximab re-initiation after a drug holiday. However, there are still several challenges regarding the widespread utilization of proactive TDM in clinical practice including the identification of the optimal drug concentration to target. Future perspectives of proactive TDM of biologics include the implementation of model-informed precision dosing and pharmacogenetics towards personalized medicine.

 Educational objectives: 

• ·       To introduce the concept of therapeutic drug monitoring (TDM) of biologics
• ·       To review the data regarding the role of proactive TDM for optimizing biologics in IBD
• ·       To describe the potential applications of proactive TDM of biologics in IBD
• ·       To identify the knowledge gaps regarding utilization of proactive TDM of biologics in IBD clinical practice
• ·       To discuss the future perspectives of proactive TDM of biologics in IBD

Proactive therapeutic drug monitoring (TDM), individualized treatment based on scheduled assessments of serum drug levels, has been proposed to optimize efficacy and safety of infliximab and other biologic drugs. However, it is unclear whether this strategy improves clinical outcomes.

In this 52-week randomised, open-label, multicenter trial, adult patients with an established diagnosis of ulcerative colitis (UC), Crohn’s disease (CD), rheumatoid arthritis (RA), spondyloarthritis (SpA), psoriatic arthritis (PsA), and psoriasis (Ps) receiving infliximab therapy for a minimum of 30 weeks were randomly assigned to proactive TDM or standard infliximab treatment. In the TDM group, infliximab dosage was adjusted according to an algorithm designed to maintain serum infliximab levels within the therapeutic range 3-8 mg/L. In the standard treatment group, infliximab dosage was based on clinical judgement.The primary endpoint was sustained disease control during the 52 week study period.

In total, 458 patients were randomised of whom 454 (UC 81, CD 66, RA 79, PsA 53, SpA 138, Ps 37) received the allocated strategy and were included in the primary analyses. The two groups were balanced regarding baseline demographics, clinical and treatment characteristics. Sustained disease control without disease worsening was observed in 167 (73.6 %) patients in the TDM group and in 127 (55.9%) patients in the standard treatment group. The estimated adjusted difference was 17.6% (95% confidence interval (CI), 9.0-26.2, p<0.001), favouring TDM (figure 1). Results were consistent in sensitivity analyses. Time to disease worsening was shorter in the standard treatment group, hazard ratio 2.1 (95% CI 1.5-2.9) (figure 2). Other secondary endpoints reflecting change in disease activity and patient reported outcomes from baseline to week 52 did not show significant differences between the two groups. During the trial, the mean infliximab dose (4.8 mg/kg) and median serum level of infliximab (5.8 mg/L) were comparable in both groups. Twenty-one (9%) patients in the TDM group and 27 (15%) in the standard treatment group developed clinically significant levels of anti-drug antibodies (≥50µg/L). Adverse events were reported in 137 (60%) and 142 (63%) patients in the TDM and standard treatment groups, respectively.

Figure 1  

Figure 2  

This large randomised controlled trial demonstrates that proactive TDM is superior to standard treatment for maintaining disease control without disease worsening in patients on maintenance therapy with infliximab. These results support implementation of proactive TDM as a general strategy during maintenance therapy with infliximab and have the potential to change clinical practice across specialities.

Perianal manifestation in Crohn’s disease patients is likely to complicate the disease course with extra intestinal manifestations, abscesses, deep anal canal ulcers, luminal fistulas and strictures, steroid resistance, and need for multiple surgeries. Diagnosis and management of perianal Crohn’s disease implies a multidisciplinary team approach. Diagnosis and definition of perianal disease requires optimal imaging modality, ideally a pelvic magnetic resonance imaging, with an exam under anesthesia (EUA). However, the lack of a definition consensus on perianal fistula in Crohn’s disease may affect standardization of therapeutic approaches and patients inclusion within clinical trial.

The synergic approach by a surgeon and a gastroenterologist is crucial with perianal Crohn’s disease. Drainage of an abscess and possible seton placement to prevent future septic complications is the basic first step of the treatemnt. Ani-TNF drug have shown the best evidence for decreasing perianal drainage and promote fistula healing. Attempting surgical repair is possibile for selected patients. Surgical strategies include subcutaneous fistulotomy, Ligation of the Intersphincteric Tract (LIFT) procedure, or endorectal advancement flap (ERAF). These surgical strategies work best when associated with anti-TNF or immunomodulation and when mild to moderate proctitis is present. More aggressive interventions include diversion of the fecal stream with loop ileostomy and proctectomy; Mesenchymal stem cells have emerged as possible effective treatment and long term results have been demonstrated by randomized clinical trial.

During the past decades, human diet has evolved towards higher intakes of processed and ultraprocessed food. We have investigated the association between these food groups and the risk of inflammatory bowel disease (IBD) in the European Prospective Investigation into Cancer and Nutrition.

413 590 participants from 8 European countries were included. Dietary data were collected at baseline from validated food frequency questionnaires. All EPIC food items were expressed as g/day and categorized according to the NOVA classification: “group 1—unprocessed or minimally processed foods”; “group 2—processed culinary ingredients”; “group 3—processed foods”; and “group 4—ultra-processed foods (UPFs)”. Because the EPIC dietary questionnaires were conceived before the NOVA classification, the food items were retrospectively categorized into this classification. Some food items collected in the EPIC questionnaires were difficult to categorize into group 3 or 4. We therefore merged them into a single category. We tested three scenarios for the estimation of the dietary content of this merged category: lower, middle and upper contents of groups 3 + 4. The association between the proportion of each NOVA group in the diet and IBD were estimated using Cox proportional hazard models to obtain Hazards Ratios (HRs) and 95% confidence intervals. We adjusted the HR for smoking status, educational level, physical activity, BMI, alcohol consumption and energy intake and stratified by centre, age at baseline (1-y interval), and sex.

After a mean follow-up of 16 years, 179 Crohn's disease (CD) and 431 ulcerative colitis (UC) cases were identified. NOVA group 1 was negatively associated with CD risk (adjusted HR for the fourth vs. the first quartile = 0.58; 95% CI = 0.35-0.95; P-trend = 0.03). Within group 1, fruit intake was the only food item to be negatively associated with the risk of IBD (adjusted HR for the fourth vs. the first quartile = 0.42; 95% CI = 0.24-0.73; P-trend = 0.003). We found numerical associations between group 3+4 and the risk of CD with the middle or upper scenarios (adjusted HRs for the fourth vs. the first quartile = 1.50; 95% CI = 0.92-2.46; P-trend = 0.12 and 1.41; 95% CI = 0.88-2.27; P-trend = 0.09 respectively). There was no association between any category of the NOVA classification and UC risk.

In the EPIC cohort, consumption of non-processed food was associated with a lower risk of CD while consumptions of processed or ultra-processed food were numerically associated with increased risk of CD. We found no association with UC.

1) To use IBD prognostic factors to improve management decisions
2) To review why intervene early if poor prognosis
3) To understand the challenges in biomarkers development
4) To learn which promisig biomarkers have been validated for clinical implementation or are undergoing validation