JAK inhibition has emerged as a promising novel therapeutic strategy in IBD. However, only a subgroup of patients responds to JAK inhibitors and there are currently no predictive markers available that predict sustained response. Our recent work strongly indicates that loss-of-function variants in the PTPN2 gene might serve as predictive markers for therapeutic effectiveness, and the main goal of this project is to define whether PTPN2 dysfunction can serve as a predictor for efficacious JAK inhibitor therapy.
The number of specialist nurses dedicated to the care and management of patients with Inflammatory Bowel Disease (IBD) is increasing across Europe, and their role is widening. Despite the increased interest in the opportunities associated with this emerging healthcare professional role, from the perspectives of both patients and clinicians, scarce evidence is available on the effectiveness of specialist nursing interventions. An in-depth review of the impact of specialist nursing interventions on the care and management of patients with IBD, and especially on the health-related quality of life (QoL), is needed.
The main outcome of interest in this context is clinical remission (the proportion of patients in whom remission is achieved or maintained). Additional outcomes are: the proportion of hospital admissions/readmissions, the length of hospital stay, clinical improvement, patients’ QoL and the effectiveness of treatment.
Perianal fistulising Crohn’s Disease (pCD) is associated with poor outcomes and impaired quality of life. It remains difficult to manage despite medical and surgical advancements, likely due to poor understanding of the underlying immunology. Previous multiparameter flow cytometry work in our lab on immune cells isolated from peripheral blood and fistula curettage samples showed expansion of iNKT cells in perianal fistula compared to peripheral blood. Furthermore, iNKTs have been suggested to have a potential role in key processes in fistula pathogenesis, namely epithelial-to-mesenchymal transition and extracellular matrix degradation. The role of iNKTs in inflammation remains poorly defined and their function in human IBD is largely unexplored. Therefore, in this experiment we aim to further define their role in the pathogenesis of perianal fistula.
Genetic studies have implicated the autophagy gene ATG16L1 and the endoplasmic stress (ER) gene XBP1 in the pathogenesis of Inflammatory Bowel Disease (IBD). Indeed, spontaneous inflammation develops in mice lacking ATG16L1 or XBP1 expression in intestinal epithelial cells (IEC). Because of the dominant role of failing autophagy and ER stress in IBD, we hypothesise that IEC stress contributes to intestinal fibrosis, gut dysmotility and pain during colitis.
This project aims, for the first time, to thoroughly comprehend the role of crucial IBD epithelial stress factors (i.e. ATG16L1 and XBP1 impairments) in enteric fibroblasts and neurons and to explore potential future intervention points.
Inflammatory Bowel Disease (IBD) results from an anomalous interaction between genetic, environmental, immunoregulatory and microbial-derived factors. IBD- associated specific mutations include genes involved in microbial recognition, such as mutations in the Toll-like receptor 4 (TLR4). Beside controlling host defence responses, TLR4 modulates enteric nervous system (ENS) activity, gut motility and repair processes following an insult. TLR4 deficiency in mice leads to significant ENS alterations, characterised by modified gut motility and susceptibility to inflammation. The findings of decreased gut catecholamine levels in IBD patients and the onset of milder experimental colitis after sympathectomy highlight the role of the nervous system as a key regulator of immune responses. Therefore, our research project aims to decode the neuroimmune interactions between the catecholaminergic system and innate immune sensor TLR4 in dinitrobenzene sulphonic acid (DNBS)-induced ileitis.
Deciphering the bioactive role of extracellular matrix fragments (matrikines) in Crohn's Disease (CD) fibrostenosis as potential therapeutic targets and biomarkers
We have pioneered in studying ex vivo extracellular matrix (ECM) remodelling, which is known for its key role in Crohn’s Disease (CD) fibrostenosis. By adding disease-relevant enzymes on the ECM of CD patients’ intestine, we identified numerous matrikines (specific ECM peptide fragments) unique in CD fibrostenosis. Peptidomics software analysis showed specific likelihood for bioactivity for 19 of those matrikines (Giuffrida et. al, unpublished data) ().
This project aims to explore the bioactivity of matrikines in CD fibrostenosis in vitro.
It is currently unknown whether diet influences inflammation in Ulcerative Colitis (UC). Observational and experimental data suggest that modulating sulphide within the luminal environment may have therapeutic potential for UC. The aim of this trial is therefore to determine whether a sulphide-reducing diet, designed to attenuate excess microbial production of potentially noxious gases in the colon, can induce remission in UC.
Comparative accuracy of TransPerineal UltraSound (TPUS) versus Magnetic Resonance Imaging (MRI) for the assessment of perianal fistulae in patients with Crohn’s Disease: a prospective observational longitudinal cohort study
Magnetic resonance imaging (MRI) is the first-line imaging modality for monitoring of perianal disease in patients with Crohn’s Disease (CD). However, its use depends on local availability, costs and expertise. Few studies are available on the role of transperineal ultrasound (TPUS). Performing MRI alone in all patients would impose a substantial expense on the health service and would represent a limitation for the many patients who cannot tolerate the procedure (e.g. owing to claustrophobia). For this reason, we urgently need a painless, non-invasive, cost-effective and widely available modality to assess perianal disease and predict disease outcomes. In this observational prospective study, we investigate the accuracy of TPUS versus pelvic MRI in the diagnosis and monitoring of medical and surgical treatment of perianal fistulae in CD patients.
Y-ECCO Interview Corner gives us the opportunity to gain insights into members of the IBD Community, what they do and how they got to where they are. For this edition, I caught up with Dr. Karen Edelblum , a scientist who has a unique and important perspective.
Karen Edelblum combines cell biology and mucosal immunology, with some stunning time-lapse microscopy. She aims to understand how we might harness immune–epithelial interactions in the treatment of Inflammatory Bowel Disease. Having trained at Vanderbilt University and the University of Chicago, she is now assistant professor at Rutgers New Jersey Medical School. We met (over an internet connection) to get her insights into IBD and the science that will move it on.
Traditionally, treatment of Crohn’s Disease (CD) has focused on symptomatic, clinical and corticosteroid-free remission. However, more recent studies have shown that endoscopic remission is associated with more favourable patient long-term outcomes [1, 2]. It has been hypothesised that more intense treatment regimens may increase the likelihood of endoscopic remission in CD patients. Previous studies (such as that performed by the DIAMOND study group) have indicated that adalimumab trough levels are higher in CD patients who achieve an endoscopic response and mucosal healing at weeks 26 and 52 [3]. Further to that, the personalised anti-TNF therapy in Crohn's Disease study (PANTS) demonstrated that low drug levels were predictive of anti-tumour necrosis factor (anti-TNF) treatment failure [4].
Various methods of dose optimisation have been postulated, such as higher induction doses, therapeutic drug monitoring (TDM) to guide dose optimisation during the maintenance phase or a clinically adjusted (CA) dose optimisation strategy.
Robin Dart