ECCO Topical Review on Biological Treatment Cycles in Crohn’s Disease

There are now a growing number of licensed biological therapies for patients with Crohn’s disease. However, there can be significant costs associated with long-term maintenance treatment, as well as some concerns about potential side-effects. As a result, there has been increasing interest in elective biological treatment discontinuation in selected patients, after a sustained period of remission. Following discontinuation, in cases of relapse, evidence to date has suggested that remission may often be regained by re-treatment with the same biological agent. Therefore, a concept has emerged in which cycles of biological therapy might be used. If this treatment strategy were to be applied in a subgroup of patients at low risk of relapse, cycling might allow a substantial number of patients to have a lower, overall therapeutic burden—ensuring decreased exposure to biological therapy but still enabling appropriate disease control.Currently, there remains uncertainty about the benefit–risk balance for using cycles of biological treatment for patients with Crohn’s disease. Accordingly, an expert panel was convened by the European Crohn’s and Colitis Organisation [ECCO] to review the published literature and agree a series of consensus practice points. The panel aimed to provide evidence-based guidance on multiple aspects of biological treatment discontinuation and cycling, including the risk of relapse after elective treatment discontinuation, predictors of probable relapse or remission, safety, patient preferences, and pharmacoeconomic aspects. Crucially, discussions about biological treatment discontinuation and cycling should be individualized, to enable shared decision-making by patients with their clinicians

Comparison of two strategies for the management of postoperative recurrence in Crohn's disease patients with one clinical risk factor: A multicentre IG-IBD study

BackgroundThe management of postoperative recurrence (POR) in Crohn's disease (CD) after ileo-colonic resection is a highly debated topic. Prophylactic immunosuppression after surgery is currently recommended in the presence of at least one clinical risk factor. ObjectiveOur aim was to determine whether early immunosuppression can be avoided and guided by endoscopy in CD patients with only one risk factor. MethodsCD patients with only one risk factor for POR, including previous intestinal resection, extensive small intestine resection (>50 cm), fistulising phenotype, history of perianal disease, and active smoking, were retrospectively included. Two groups were formed based on whether immunosuppression was started immediately after surgery ("prophylaxis group") or guided by endoscopy ("endoscopy-driven group"). Primary endpoints were rates of any endoscopic recurrence (Rutgeerts >= i2a) and severe endoscopic recurrence (i4) within 12 months after surgery. Secondary outcomes were clinical recurrence rates at 6, 12 and 24 months after surgery. ResultsA total of 195 patients were enroled, of whom 61 (31.3%) received immunoprophylaxis. No differences between immunoprophylaxis and the endoscopy-driven approach were found regarding any endoscopic recurrence (36.1% vs. 45.5%, respectively, p = 0.10) and severe endoscopic recurrence (9.8% vs. 15.7%, respectively, p = 0.15) at the first endoscopic evaluation. Clinical recurrence rates were also not statistically different (p = 0.43, p = 0.09, and p = 0.63 at 6, 12, and 24 months, respectively). ConclusionsIn operated CD patients with only one risk factor for POR, immediate immunoprophylaxis does not decrease the rate of early clinical and endoscopic recurrence. Prospective studies are needed to confirm our results

The profibrogenic role of neutrophil extracellular traps in stenotic Crohn's disease: a new antifibrotic target

BACKGROUND: Neutrophil extracellular traps (NETs) are structures of DNA filaments and protein granules, extruded by neutrophils after insults in a PAD4-dependent manner. In autoimmune events, their release occurs early during inflammation, further aggravating tissue injury and presumably contributing to fibrosis. Our aim was to investigate the potential profibrotic effect of NETs in stenotic Crohn’s disease (CD). METHODS: Immunofluorescence (IF) for PAD4, NETs markers and fibroblast activation protein (FAP) was performed on resected ileum derived from patients with stricturing CD. Human intestinal fibroblasts (HIF) were extracted from unaffected CD ileum. A CCD-18Co fibroblast line was used as confirmation. In vitro co-cultures of subconfluent HIF with NETs were performed for 24 hours, and RNA extracted for sequencing. Soluble collagen released in culture medium was quantified with SIRCOL®. Migratory activity was investigated with scratch test. IF intensity of collagen and FAP was quantified using Operetta®. Transfection of CCD-18co cells with NF-kB-luciferase reported plasmid was performed to evaluate the TLR2/NF-kB pathway. Specific inhibitors (C29 and CAPE) were used to block TLR2 and NF-kB activity, respectively. Finally, a chronic DSS mice model of intestinal fibrosis with selective PAD4 knock-out in neutrophils (PAD4fl/flMRP8Cre+) was used as confirmation. Picrosirius red staining and SIRCOL® were used to quantify the collagen amount after sacrifice. RESULTS: IF on inflamed ileum showed clusters of NETs close to FAP+ fibroblasts, suggesting in vivo interactions. Transcriptomics demonstrated an upregulation of profibrotic genes and toll-like pathways (p<0.05) in the group of HIF stimulated with NETs. Increased proliferation rate, slower wound healing ability and higher collagen release in the medium were observed in NETs group, as well as higher IF expression of collagens and FAP. Transfection showed significant upregulation (p=0.015) of NF-kB in NETs group, whereas its expression and soluble collagen release decreased using C29 and CAPE. Accordingly, phospho-NF-kB and MyD88 proteins were increased in NETs group. A significantly lower amount of collagen was measured in the colon of PAD4-knocked out mice both with Picrosirius red (p=0.04) and SIRCOL® (p=0.008), as well as reduced FAP+ fibroblasts at IF. CONCLUSION: NETs may represent an early trigger of fibroblast activation in the intestine via the TLR2/NF-kB axis. As NETs are also early players during inflammation, blocking PAD4 might improve both inflammation and fibrogenesis in CD

The Role of Citrullination in Inflammatory Bowel Disease: A Neglected Player in Triggering Inflammation and Fibrosis?

Citrullination is a posttranslational modification of proteins mediated by a specific family of enzymes called peptidylarginine deiminases (PAD). Dysregulation of these enzymes is involved in the etiology of various diseases, from cancer to autoimmune disorders. In inflammatory bowel disease (IBD), data for a role of citrullination in the disease process are starting to accumulate at different experimental levels including gene expression analyses, RNA, and protein quantifications. Most data have been generated in ulcerative colitis, but data in Crohn disease are lacking so far. In addition, the citrullination of histones is the fundamental process promoting inflammation through the formation of neutrophil extracellular traps (NETs). Interestingly, NETs have also been shown to activate fibroblasts into myofibroblasts in fibrotic interstitial lung disease. Therefore, citrullination merits more thorough study in the bowel to determine its role in driving disease complications such as fibrosis. In this review we describe the process of citrullination and the different players in this pathway, the role of citrullination in autoimmunity with a special focus on IBD, the emerging role for citrullination and NETs in triggering fibrosis, and, finally, how this process could be therapeutically targeted.status: Published onlin

Extending Security-by-Contract with Quantitative Trust on Mobile Devices

Security-by-Contract (S?C) is a novel paradigm providing security assurances for mobile applications. In this work, we present an extension of S?C enriched with an au- tomatic trust management infrastructure. Indeed, we enhance the already existing architecture by adding new modules and configurations for contracts managing. At deploy-time, our system decides the run-time configuration depending on the credentials of the contract provider. Roughly, the run-time environment can both enforce a security policy and monitor the declared contract. According to the actual behaviour of the running program our architecture updates the trust level associated with the contract provider. The main advantage of this method is an automatic management of the level of trust of software and contract releaser

Results of the Seventh Scientific Workshop of ECCO: Precision Medicine in IBD—What, Why, and How

Many diseases that affect modern humans fall in the category of complex diseases, thus called because they result from a combination of multiple aetiological and pathogenic factors. Regardless of the organ or system affected, complex diseases present major challenges in diagnosis, classification, and management. Current forms of therapy are usually applied in an indiscriminate fashion based on clinical information, but even the most advanced drugs only benefit a limited number of patients and to a variable and unpredictable degree. This 'one measure does not fit all' situation has spurred the notion that therapy for complex disease should be tailored to individual patients or groups of patients, giving rise to the notion of 'precision medicine' [PM]. Inflammatory bowel disease [IBD] is a prototypical complex disease where the need for PM has become increasingly clear. This prompted the European Crohn's and Colitis Organisation to focus the Seventh Scientific Workshop on this emerging theme. The articles in this special issue of the Journal address the various complementary aspects of PM in IBD, including what PM is; why it is needed and how it can be used; how PM can contribute to prediction and prevention of IBD; how IBD PM can aid in prognosis and improve response to therapy; and the challenges and future directions of PM in IBD. This first article of this series is structured on three simple concepts [what, why, and how] and addresses the definition of PM, discusses the rationale for the need of PM in IBD, and outlines the methodology required to implement PM in IBD in a correct and clinically meaningful way