Defining biological remission in Crohn's disease: interest, challenges and future directions.

peer reviewedIn Crohn's disease, the treat-to-target strategy has been highly encouraged and became a standard of care. In this context, defining the target (remission) constitutes a major stake which fuels the literature. Currently, clinical remission (symptoms control) is no longer the only objective of treatments since it does not allow to well control inflammation-induced tissue damage. The introduction of endoscopic remission as a therapeutic target was clearly a progress but this examination remains invasive, costly, not well accepted by patients and does not allow a tight control of disease activity. More fundamentally, morphological techniques (eg, endoscopy, histology, ultrasonography) are limited since they do not evaluate the biological activity of the disease but only its consequences. Besides, emerging evidence suggest that biological signs of disease activity could better guide treatment decisions than clinical parameters. In this context, we stress the necessity to define a novel treatment target: biological remission. Based on our previous work, we propose a conceptual definition of biological remission which goes beyond the classical normalisation of inflammatory markers (C-reactive protein and faecal calprotectin): absence of biological signs associated with the risk of short-term relapse and mid/long-term relapse. The risk of short-term relapse seems essentially characterised by a persistent inflammatory state while the risk of mid/long-term relapse implicates a more heterogeneous biology. We discuss the interest of our proposal (guiding treatment maintenance, escalation or de-escalation) but also the fact that its clinical implementation would require overcoming major challenges. Finally, future directions are proposed to better define biological remission

Is it time to include older adults in inflammatory bowel disease trials? A call for action

peer reviewedThe therapeutic management of older patients with inflammatory bowel disease (IBD) is challenging, particularly because of the absence of evidence-based guidelines for these patients, who seem to frequently be excluded from clinical trials. In this systematic review we investigated the exclusion of older patients with IBD from phase 3 studies registered on PubMed and ClinicalTrials.gov, by assessing the upper limit of age exclusion criteria and the percentage of patients older than 65 years included in the trials. Exclusion criteria other than age were also recorded, and comorbidities were analysed separately. Our review of 222 phase 3 studies shows that older patients are frequently excluded from IBD clinical trials because of their age, which was used as an exclusion criterion in 129 (58%) of the 222 assessed trials. Of the 32 trials that detailed the percentage of included patients who were 65 years or older, only 763 (5·4%) patients of the 14 124 patients included were older than 65 years. In addition to age, patients were also excluded because of comorbidities (mainly renal, hepatic, and cardiovascular, and used as an exclusion criterion in 76% of trials), a history of dysplasia (45% of trials), and previous treatment for IBD (19% of trials). We propose a three-step process that should enable the inclusion of all older patients in IBD clinical trials, regardless of their age, comorbidities, and frailty

Review article: distinctions between ileal and colonic Crohn's disease: from physiology to pathology.

peer reviewedBACKGROUND: Ileal and colonic Crohn's disease seem to be two separate entities. AIMS: To describe the main physiological distinctions between the small and the large intestine and to analyse the differences between ileal and colonic Crohn's disease. METHODS: The relevant literature was critically examined and synthesised. RESULTS: The small and large intestine have fundamental distinctions (anatomy, cellular populations, immune defence, microbiota). The differences between ileal and colonic Crohn's disease are highlighted by a heterogeneous body of evidence including clinical features (natural history of the disease, efficacy of treatments, and monitoring), epidemiological data (smoking status, age, gender) and biological data (genetics, microbiota, immunity, mesenteric fat). However, the contribution of these factors to disease location remains poorly understood. CONCLUSION: The classification of ileal and colonic Crohn's disease as distinct subphenotypes is well supported by the literature. Understanding of these differences could be exploited to develop more individualised patient care

Impact of the Exposome on the Epigenome in Inflammatory Bowel Disease Patients and Animal Models

peer reviewedInflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract that encompass two main phenotypes, namely Crohn’s disease and ulcerative colitis. These conditions occur in genetically predisposed individuals in response to environmental factors. Epigenetics, acting by DNA methylation, post-translational histones modifications or by non-coding RNAs, could explain how the exposome (or all environmental influences over the life course, from conception to death) could influence the gene expression to contribute to intestinal inflammation. We performed a scoping search using Medline to identify all the elements of the exposome that may play a role in intestinal inflammation through epigenetic modifications, as well as the underlying mechanisms. The environmental factors epigenetically influencing the occurrence of intestinal inflammation are the maternal lifestyle (mainly diet, the occurrence of infection during pregnancy and smoking); breastfeeding; microbiota; diet (including a low-fiber diet, high-fat diet and deficiency in micronutrients); smoking habits, vitamin D and drugs (e.g., IBD treatments, antibiotics and probiotics). Influenced by both microbiota and diet, short-chain fatty acids are gut microbiota-derived metabolites resulting from the anaerobic fermentation of non-digestible dietary fibers, playing an epigenetically mediated role in the integrity of the epithelial barrier and in the defense against invading microorganisms. Although the impact of some environmental factors has been identified, the exposome-induced epimutations in IBD remain a largely underexplored field. How these environmental exposures induce epigenetic modifications (in terms of duration, frequency and the timing at which they occur) and how other environmental factors associated with IBD modulate epigenetics deserve to be further investigated

Precision medicine and drug optimization in adult inflammatory bowel disease patients

Inflammatory bowel diseases (IBD) encompass two main entities including ulcerative colitis and Crohn’s disease. Although having a common global pathophysiological mechanism, IBD patients are characterized by a significant interindividual heterogeneity and may differ by their disease type, disease locations, disease behaviours, disease manifestations, disease course as well as treatment needs. Indeed, although the therapeutic armamentarium for these diseases has expanded rapidly in recent years, a proportion of patients remains with a suboptimal response to medical treatment due to primary non-response, secondary loss of response or intolerance to currently available drugs. Identifying, prior to treatment initiation, which patients are likely to respond to a specific drug would improve the disease management, avoid unnecessary side effects and reduce the healthcare expenses. Precision medicine classifies individuals into subpopulations according to clinical and molecular characteristics with the objective to tailor preventative and therapeutic interventions to the characteristics of each patient. Interventions would thus be performed only on those who will benefit, sparing side effects and expense for those who will not. This review aims to summarize clinical factors, biomarkers (genetic, transcriptomic, proteomic, metabolic, radiomic or from the microbiota) and tools that could predict disease progression to guide towards a step-up or top-down strategy. Predictive factors of response or non-response to treatment will then be reviewed, followed by a discussion about the optimal dose of drug required for patients. The time at which these treatments should be administered (or rather can be stopped in case of a deep remission or in the aftermath of a surgery) will also be addressed. IBD remain biologically complex, with multifactorial etiopathology, clinical heterogeneity as well as temporal and therapeutic variabilities, which makes precision medicine especially challenging in this area. Although applied for many years in oncology, it remains an unmet medical need in IBD