The role of fibroblasts in the pathogenesis of Crohn’s Disease-associated fistulas and in mesenchymal stem cell therapy  

Ramona Bruckner © Ramona Bruckner

Aim of the research

Perianal fistulas are a severe and frequent complication in Crohn’s Disease (CD) patients, significantly affecting their quality of life. High recurrence rates, incomplete fistula healing and non-responding patients make the treatment challenging. Despite some novel insights, current knowledge about the pathogenesis of fistula formation is still limited. Fibroblasts are abundantly present in fistulas and were recently reported to regulate Th1 cell activity in Inflammatory Bowel Disease (IBD). Our hypothesis is that fibroblasts act as the key drivers of this disease complication by regulating inflammatory cell recruitment. We will investigate which pro-inflammatory cytokines and chemoattractants are produced by fistula-derived fibroblasts and how they influence recruitment of immune cells, leading to sustained inflammation. Our second hypothesis is that mesenchymal stem cells (MSCs) can normalise this fibroblast-driven pro-inflammatory environment.

PTPN2 and TiO2 in the pathogenesis of Inflammatory Bowel Disease  

Aim of the research

Titanium dioxide (TiO2) may play a pivotal role in the onset and perpetuation of chronic intestinal inflammation. These effects may be genetically triggered, and variations in IBD risk genes, such as PTPN2, may contribute critically to the detrimental effect of TiO2 in vivo. For these reasons, we will study the combined effects of the presence of disease-associated genetic PTPN2 variations and TiO2 microparticles on the development of chronic intestinal inflammation and on inflammasome activity, as well as the subsequent consequences for the host immune system, in particular innate immune responses. The study will demonstrate the relevance of TiO2 in the pathogenesis of intestinal inflammation in vivo. To address the aforementioned aims, we will:

1. Analyse whether PTPN2-mediated inflammasome activation can control TiO2-induced intestinal inflammation.
2. Demonstrate whether the presence of the disease-associated PTPN2 variant affects NLRP3 inflammasome activation and intestinal inflammatory responses to TiO2 in IBD patients.

Charlotte Hedin © ECCO

Early clinical trials, the advent of biologics and the IBD Nurse and how the clinical presentation of IBD has changed over a 46-year career: The interviewee in this issue is Professor David Rampton, who has had a long career as an IBD clinician and researcher in East London. Respected by colleagues and patients alike, his career has spanned an era during which much has changed in IBD.

Rates and characteristics of postcolonoscopy colorectal cancer in the Swedish IBD population: What are the differences from a non-IBD population?

Stjärngrim J, Ekbom A, Hammar U, Hultcrantz R, Forsberg AM

Gut 2018 Dec 15; doi: 10.1136/gutjnl-2018-316651

Introduction

Rohit Rao  © Rohit Rao

Individuals with IBD have an increased risk of colorectal cancer (CRC) [1, 2]. In an effort to address this, societal guidelines recommend surveillance colonoscopy 8–10 years after diagnosis and at varying intervals thereafter, depending on risk [3, 4]. A 2017 Cochrane systematic review [5] demonstrated a benefit in this strategy, noting reductions in the development of both CRC and the rate of CRC‐associated death. Despite this, dysplasia detection is challenging and CRC still accounts for 10%–15% of all IBD deaths [6, 7]. Of further concern is the reported increased rate of post-colonoscopy colorectal cancer (PCCRC) in IBD. 

Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn’s disease: A prospective, multicentre, cohort study

Kennedy NA, Heap GA, Green HD, Hamilton B, Bewshea C, Walker GJ, Thomas A, Nice R, Perry MH, Bouri S, Chanchlani N, Heerasing NM, Hendy P, Lin S, Gaya DR, Cummings JRF, Selinger CP, Lees CW, Hart AL, Parkes M, Sebastian S, Mansfield JC, Irving PM, Lindsay J, Russell RK, McDonald TJ, McGovern D, Goodhand JR, Ahmad T, UK Inflammatory Bowel Disease Pharmacogenetics Study Group*

Lancet Gastroenterol Hepatol. 2019;4:341–53

Introduction

Misha Kabir  © Misha Kabir

The anti-TNF monoclonal antibodies infliximab and adalimumab have been integral to the management of Crohn’s Disease over the past two decades. However, primary non-response and secondary loss of response in the first year of treatment remain common, at 10%–40% [1–3] and 23%–46% [4] respectively. Immunogenicity has been implicated as an important predictive factor for anti-TNF therapy failure. However, target-to-treat drug and anti-drug antibody concentrations have not yet been validated in an adequately powered prospective study. The Personalised Anti-TNF Therapy in Crohn’s Disease Study (PANTS) aimed to investigate the factors that predict primary non-response, non-remission and adverse events with anti-TNF therapy in luminal Crohn’s Disease.

Early combined immunosuppression may be effective and safe in older patients with Crohn’s disease: post hoc analysis of REACT

Singh S, Stitt LW, Zou G, et al.

Aliment Pharmacol Ther. 2019;49:1188–94.

Introduction

Georgina Cunningham  © Georgina Cunningham

Due to the ageing population and the chronicity of the disease, increasing numbers of patients with Inflammatory Bowel Disease (IBD) are now over the age of 60 [1]. The management of IBD in this group poses some challenges, mainly centered on the balance between risk of immunosuppression and the burden of active disease [2]. Although older IBD patients usually display a more indolent disease course, they are more likely to be hospitalised and have higher in-hospital mortality than their younger counterparts [3]. There is no doubt that there is room for improvement in our management of IBD in elderly patients, and guidance is needed to help physicians decide whether more aggressive treatment strategies, widely accepted in certain younger IBD patients [4], are also warranted in this cohort, and especially those at high risk of disease complications.

Dominik Bettenworth © ECCO

Dear Y-ECCO Friends,

One of the main tasks of the Young ECCO Committee (Y-ECCO) is to offer Y-ECCO Members opportunities to expand their scientific skills and develop their own research projects. Following the last Y-ECCO Basic Science Workshop in Copenhagen, which was a great success in terms of attendance and participant feedback, plans for the 6th Y-ECCO Basic Science Workshop at the 15th Congress of ECCO in Vienna 2020 are already in full swing. The potential for the successful establishment of intestinal organoids will substantially expand the basic research on Inflammatory Bowel Diseases (IBD). In addition, experimental research should always focus on an effective translation of experimental results into the clinic in order to improve the treatment of our IBD patients in the long term. Therefore, organoids and translational basic science research will be the two main topics of the 6th Y-ECCO Basic Science Workshop. Fortunately, we were able to expand the structure of the workshop so that three awardees of the ECCO Research Fellowships Programme will present their results at the workshop and will also be available to answer all your questions regarding the pros and cons of a fellowship. 

Magali Svrcek © ECCO

Immune checkpoints (ICK) are downregulators of T cell immunity. Immune checkpoint inhibitors (ICKi), by blocking the co-inhibitory receptors on T cells to activate their cytotoxic immune function, have become a major therapeutic tool in oncology, notably for the treatment of metastatic melanoma, non-small cell lung carcinoma, renal cell carcinoma, urothelial carcinoma and mismatch repair (MMR) deficient/microsatellite-unstable tumours. In particular, therapeutic monoclonal antibodies have emerged against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), which primarily inhibits T cell activation, and programmed cell death 1 (PD-1), which limits the effector function of activated T cells in the periphery. Food and Drug Administration-approved ICKi include ipilimumab (CTLA-4 inhibitor), pembrolizumab and nivolumab (anti-PD-1) and atezolizumab (anti-PD-L1).

Johan Van Limbergen  © ECCO

Konstantinos Gerasimidis © ECCO

Johan Van Limbergen^1,2, Konstantinos Gerasimidis³

Crohn’s Disease (CD) is increasing in incidence worldwide [1]. In spite of increased use of immune suppression, which has markedly changed the need for in-hospital care, paediatric CD remains associated with considerable morbidity as well as increased mortality [2, 3]. The onset of disease in childhood and adolescence often interferes with growth and development, both physically and psychologically. In a subset of patients, the progressive nature of disease may be associated with a fibrotic phenotype that does not respond adequately to the currently available immune suppressive medications, yet use of these medications is still associated with increased risk of myelosuppression, opportunistic infections, immune-mediated phenomena and malignancy [2, 4–6]. 

Yves Panis © ECCO

As chair of the S-ECCO Committee, it is my pleasure to introduce a newly elected member for 2019, Pär Myrelid, who will stay for 3 years, up to February 2022. Thus, the current members of the S-ECCO Committee are: Michel Adamina (Winterthur, Switzerland) (who will be, after me, the next chair), Yves Panis (Clichy, France) (chair up to February 2020), Christianne Buskens (Amsterdam, who will stay up to February 2021), Hagit Tulchinsky (Tel Aviv, who will also stay up to February 2021) and Pär Myrelid.