Citrullination is a post-translational modification of proteins, mediated by enzymes called PADs (peptidylarginine deiminases). PAD4 has recently been shown to citrullinate histone 3 (H3cit) in the nucleus, leading to the expulsion of extracellular traps from neutrophils (NETs), whose presence in Crohn’s Disease (CD) is debated.
The aim of this project is to investigate the role of PAD4 in inflammatory and fibrotic contexts of ileal CD.
In the Personalised Anti-TNF Therapy in Crohn’s Disease (PANTS) prospective cohort study, we followed 1,610 patients with Crohn’s Disease treated with infliximab or adalimumab for three years. About one in four patients experienced primary non-response and one-third of initial responders lost response, leaving only one-third in remission at one year.
A limited number of proteomic markers have been implicated in anti-TNF treatment failure, but their relative effects and interactions have not been fully explored. We aim:
To identify novel protein biomarkers linked to intestinal inflammation and immunity that influence pharmacokinetic or pharmacodynamic related primary non-response and non-remission at one year, using two multiplex Olink proteomic panels.
Validate previously postulated protein markers associated with anti-TNF primary non-response and non-remission at one year, including TREM-1, oncostatin M, Vitamin D, ASCA, ANCA and anti-OmpC.
CCL20 and its cognate receptor CCR6 are dysregulated in the colonic mucosa and serum of IBD patients; their genes have been identified as susceptibility genes for IBD and an anti-CCL20 neutralizing antibody has been reported to be beneficial in TNBS-induced colitis. Our working hypothesis is that blocking the CCL20-CCR6 axis represents a novel and promising approach to IBD therapy by limiting neutrophil recruitment to the inflamed tissues and by restoring the balance of effector/regulatory T cells. Accordingly, our aim is the preclinical validation of small-molecule CCR6 antagonists as potential drug candidates for the treatment of IBD.
Local mesenchymal stromal cell (MSC) therapy is approved for the treatment of Crohn’s Disease-associated perianal fistulas. However, little is known about the mechanism(s) of action of local MSC therapy. In this project we intend to unravel the engraftment and immunoregulatory effects of local MSC therapy in patients with refractory IBD.
Fernando Magro is Consultant in Gastroenterology and Director of Pharmacology at the University Hospital São João Porto, Portugal. In addition Fernando is also Associate Editor of the UEG Journal and founder of the Portuguese IBD Group. As he started his term as new Education Officer at ECCO'20 we wanted to provide the ECCO News readers with an exclusive interview with him.
Once more, the interview was recorded and can be listened to by clicking on the button below. We hope you will enjoy the introduction to ECCO's Education Officer.
Britta Siegmund is Medical Director of the Medical Department, Division of Gastroenterology, Infectiology and Rheumatology, Charité – Universitätsmedizin Berlin and holds many other important national and international roles within the scientific and medical communities. She has an extensive publication record in the mucosal immunology of IBD. She is also President-Elect of ECCO.
Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn’s disease: retrospective long-term follow-up of the LIR!C trial
Stevens TW, Haasnoot ML, D’Haens GR, Buskens CJ, De Groof EJ, Eshuis EJ, Gardenbroek TJ, Mol B, Stokkers PCF, Bemelman WA, Ponsioen CY on behalf of the LIR!C study group
Lancet Gastroenterol Hepatol 2020 Jun 30;S2468-1253(20)30117-5. doi: 10.1016/S2468-1253(20)30117-5. Online ahead of print.
The positioning of medical therapies in the management of Crohn’s Disease (CD) continues to be debated [1] whilst surgery is reserved for cases with disease complications or failure of medical therapy. The LIR!C trial [2] provided evidence for surgical resection as an alternative to infliximab (IFX) in the management of localised terminal ileitis, a common presentation of CD [3].
Briefly, the LIR!C trial reported quality of life scores (IBDQ) among 143 adult patients with terminal ileitis (<40 cm) who underwent randomisation to IFX induction/maintenance or ileocaecal resection. Patients were recruited from 29 secondary and tertiary Dutch and British centres. Exclusion criteria included non-inflammatory disease, prestenotic dilatation, abscess and previous surgery. Inclusion criteria included failing at least three months of conventional therapy [immunomodulator (IM) and/or corticosteroid (CS)] [2]
First introduced by Svartz in 1942, 5-aminosalicylates (5-ASAs) are a well-established and effective first-line therapy for the induction and maintenance of remission in patients with mild-to-moderate Ulcerative Colitis (UC). They remain the most frequently prescribed medication for UC and are known to be effective and well tolerated [1]. Between 87% and 98% of UC patients receive 5-ASA treatment within the first year of diagnosis and 60%–87% continue on this treatment at ten years [2, 3].
Escalation to anti-metabolites (thiopurines or methotrexate) and/or biologic or small molecule therapy is often required for UC patients with a more aggressive disease course. Whilst it is now accepted that discontinuing 5-ASA therapy when escalating to a biologic is not associated with adverse outcomes, less is known about the therapeutic benefit of continuation of 5-ASAs with an antimetabolite [2, 4].
Singh et al conducted a retrospective cohort study to evaluate the pattern of 5-ASA use in patients with UC following escalation to an antimetabolite. The study evaluated patients escalated to antimetabolite therapy (stopping 5-ASA vs short-term 5-ASA use for <6 months vs persistent 5-ASA use for >6 months) and compared the risk of clinically important complications based on the pattern of 5-ASA use in these patients. They hypothesised that continuing 5-ASA therapy would not be more beneficial than stopping it.
The aetiopathogenesis of CD is multifactorial but includes the interaction between the microbiome and the host’s immune response. Up to 80% of patients with Crohn’s Disease (CD) require surgery during their lifetime and many factors are associated with postoperative recurrence (POR). Differential abundance of bacterial species is seen in patients with IBD compared with healthy individuals and several studies have suggested an association between microbiota composition and CD recurrence [1–3]. Altered mucosal gene expression and abundance of specific microbiota are associated with, and specific to, ileal CD [4].
I hope you are all doing well and have enjoyed your summer break – even if for most of us this probably wasn’t the vacation we had hoped for. I got to explore new areas of my own country, Denmark, which was surprisingly pleasant despite the Danish weather not giving us too much sun and warmth.
Gabriele Dragoni
Neil Chanchlani
Simona Bertoni
Marieke Barnhoorn
Ignacio 
Charlotte Hedin 
Johan Burisch