Summary
Interleukin (IL)‐36α, IL‐36β and IL‐36γ are expressed highly in skin and are involved in the pathogenesis of psoriasis, while the antagonists IL‐36Ra or IL‐38, another potential IL‐36 ...inhibitor, limit uncontrolled inflammation. The expression and role of IL‐36 cytokines in rheumatoid arthritis (RA) and Crohn's disease (CD) is currently debated. Here, we observed that during imiquimod‐induced mouse skin inflammation and in human psoriasis, expression of IL‐36α, γ and IL‐36Ra, but not IL‐36β and IL‐38 mRNA, was induced and correlated with IL‐1β and T helper type 17 (Th17) cytokines (IL‐17A, IL‐22, IL‐23, CCL20). In mice with collagen‐induced arthritis and in the synovium of patients with RA, IL‐36α, β, γ, IL‐36Ra and IL‐38 were all elevated and correlated with IL‐1β, CCL3, CCL4 and macrophage colony‐stimulating factor (M‐CSF), but not with Th17 cytokines. In the colon of mice with dextran sulphate sodium‐induced colitis and in patients with CD, only IL‐36α, γ and IL‐38 were induced at relatively low levels and correlated with IL‐1β and IL‐17A. We suggest that only a minor subgroup of patients with RA (17–29%) or CD (25%) had an elevated IL‐36 agonists/antagonists ratio, versus 93% of patients with psoriasis. By immunohistochemistry, IL‐36 cytokines were produced by various cell types in skin, synovium and colonic mucosa such as keratinocytes, CD68+ macrophages, dendritic/Langerhans cells and CD79α+ plasma cells. In primary cultures of monocytes or inflammatory macrophages (M1), IL‐36β and IL‐36Ra were produced constitutively, but IL‐36α, γ and IL‐38 were produced after lipopolysaccharide stimulation. These distinct expression profiles may help to explain why only subgroups of RA and CD patients have a potentially elevated IL‐36 agonists/antagonists ratio.
Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel diseases (IBDs), are characterized by high levels of IL-22 production. Rodent studies revealed that this cytokine is ...protective during colitis but whether this is true in IBDs is unclear. We show here that levels of the soluble inhibitor of IL-22, interleukin 22-binding protein (IL-22BP), are significantly enhanced during IBDs owing to increased numbers of IL-22BP-producing eosinophils, that we unexpectedly identify as the most abundant source of IL-22BP protein in human gut. In addition, using IL-22BP-deficient rats, we confirm that endogenous IL-22BP is effective at blocking protective actions of IL-22 during acute colitis. In conclusion, our study provides new important insights regarding the biology of IL-22 and IL-22BP in the gut and indicates that protective actions of IL-22 are likely to be suboptimal in IBDs thus making IL-22BP a new relevant therapeutic target.
Background and aims: Early endoscopic recurrence is frequent after intestinal resection for Crohn’s disease. Bacteria are involved, and probiotics may modulate immune responses to the intestinal ...flora. Here we tested the probiotic strain Lactobacillus johnsonii LA1 in this setting. Patients and methods: This was a randomised, double blind, placebo controlled study. Patients were eligible if they had undergone surgical resection of <1 m, removing all macroscopic lesions within the past 21 days. Patients were randomised to receive two packets per day of lyophilised LA1 (2×109 cfu) or placebo for six months; no other treatment was allowed. The primary endpoint was endoscopic recurrence at six months, with grade >1 in Rutgeerts’ classification or an adapted classification for colonic lesions. Endoscopic score was the maximal grade of ileal and colonic lesions. Analyses were performed primarily on an intent to treat basis. Results: Ninety eight patients were enrolled (48 in the LA1 group). At six months, endoscopic recurrence was observed in 30/47 patients (64%) in the placebo group and in 21/43 (49%) in the LA1 group (p = 0.15). Per protocol analysis confirmed this result. Endoscopic score distribution did not differ significantly between the LA1 and placebo groups. There were four clinical recurrences in the LA1 group and three in the placebo group. Conclusion:L johnsonii LA1 (4×109 cfu/day) did not have a sufficient effect, if any, to prevent endoscopic recurrence of Crohn’s disease.
Background and Aims:
Anal fistula plug AFP is a bioabsorbable bioprosthesis used in ano-perineal fistula treatment. We aimed to assess efficacy and safety of AFP in fistulising ano-perineal Crohn’s ...disease FAP-CD.
Methods:
In a multicentre, open-label, randomised controlled trial we compared seton removal alone control group with AFP insertion AFP group in 106 Crohn’s disease patients with non- or mildly active disease having at least one ano-perineal fistula tract drained for more than 1 month. Patients with abscess collection ≥ 3mm on magnetic resonance imaging or recto-vaginal fistulas were excluded. Randomisation was stratified in simple or complex fistulas according to AGA classification. Primary end point was fistula closure at Week 12.
Results:
In all, 54 patients were randomised to AFP group control group 52. Median fistula duration was 23 10–53 months. Median Crohn’s Disease Activity Index at baseline was 81 45–135. Fistula closure at Week 12 was achieved in 31.5% patients in the AFP group and in 23.1 % in the control group (relative risk RR stratified on AGA classification: 1.31; 95% confidence interval: 0.59–4.02; p = 0.19). No interaction in treatment effect with complexity stratum was found; 33.3% of patients with complex fistula and 30.8% of patients with simple fistula closed the tracts after AFP, as compared with 15.4% and 25.6% in controls, respectively RR of success = 2.17 in complex fistula vs RR = 1.20 in simple fistula; p = 0.45. Concerning safety, at Week 12, 17 patients developed at least one adverse event in the AFP group vs 8 in the controls p = 0.07.
Conclusion:
AFP is not more effective than seton removal alone to achieve FAP-CD closure.
Neuro‐glial crosstalk in inflammatory bowel disease Neunlist, M.; Van Landeghem, L.; Bourreille, A. ...
Journal of internal medicine,
June 2008, Letnik:
263, Številka:
6
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
.
Inflammatory bowel disease (IBD) is a multifactorial disease in which environmental, immune and genetic factors are involved in the pathogenesis. Although biological therapies (antibodies ...anti‐tumour necrosis factor‐α or anti‐integrin) have considerably improved the symptoms and quality of life of IBD patients, some drawbacks have emerged limiting their long‐term use. In addition, prevention of relapses and treatment of resistant ulcers remains a clinical challenge. In this context, a better understanding of the pathophysiology of IBD and the development of novel therapeutic intervention would benefit from further basic and preclinical research into the role of the cellular microenvironment and the interaction between its cellular constituents. In this context, the role of the enteric nervous system (ENS) in the regulation of the intestinal epithelial barrier (IEB) and the gut immune response has fuelled an increased interest in the last few years. Recent advances, summarized in this review, have highlighted the ENS as playing a key role in the control of IEB functions and gut immune homeostasis, and that alterations of the ENS could be directly associated in the development of IBD and its associated symptoms.
Inflammatory Bowel Diseases (IBD) affect psychological, family, social and professional dimensions of patients' life, leading to disability which is essential to quantify as part of Patient-Reported ...Outcomes (PROs) newly included in the targets to reach in IBD patients. Up to now, the IBD-Disability Index (IBD-DI) was the only validated tool to assess disability, but it is not appropriate for use in clinical practice. The IBD Disk was developed, a shortened and self-administered tool, adapted from the IBD-DI, in order to give immediate representation of patient-reported disability. However, the IBD Disk has not been validated yet in clinical practice. The aims of the VALIDate study are to validate this tool in a large population of IBD patients and to compare it to the already validated IBD-DI.
The VALIDate study is an ongoing multicentric prospective cohort study launched in April 2018 in 3 French University Hospitals (Nantes, Rennes, Angers), with an objective to reach a sample of 400 patients over a period inclusion of 6 months. Each patient will fill in the two questionnaires IBD Disk and IBD-DI at baseline, then between 3 and 12 months later, during a follow-up visit. Clinical and socio-demographic data will also be collected. During these two consultations, gastroenterologists and patients will evaluate disease activity thanks to a semi-quantitative 4-grade scale, named respectively PGA (Physician Global Assessment) and PtGA (Patient Global Assessment). This cohort will allow to evaluate the validity of the IBD Disk with respect to the IBD-DI in order to generalize its use for clinical practice. Other psychometric criteria of the IBD Disk will also be analysed as its reliability or its discriminant capacity. Close attention will nonetheless be needed to minimize the number of lost to follow-up patients between baseline and follow-up.
The VALIDate study is the study designed to validate the IBD Disk, a visual tool easily useable in daily practice to assess disability in IBD patients. The results of this trial should enable the diffusion of this tool.
The trial is registered in ClinicalTrials.Gov with registration number NCT03590639. First posted: July 18, 2018.
Background
Neuroplastic changes in the enteric nervous system (ENS) observed during IBD might participate in physiopathological processes. Vasoactive intestinal polypeptide has been shown to be ...involved in intestinal inflammation and barrier functions. We aimed to investigate the modulation of VIP expression in colonic biopsies of IBD patient, the ability of soluble factors from biopsies to reproduce in vitro these modulations and identify soluble factors responsible.
Methods
VIP and cytokines mRNA expressions were assessed in colonic biopsies of healthy subjects (HS) and IBD patients from inflamed (I) and non‐inflamed areas (NI). Supernatants (SUP) of biopsies were applied to primary culture of ENS and VIP and cytokines mRNA expressions were assessed. The role of cytokines in SUP induced changes in VIP expression was evaluated.
Key Results
VIP mRNA expression was lower in biopsies of patients with Crohn's disease (CD) than Ulcerative Colitis (UC) but unchanged as compared to HS. VIP mRNA and protein expression were lower in primary culture of ENS incubated with SUP‐CD than with SUP‐UC. Furthermore, in CD but not UC, SUP‐I reduced VIP expression in the ENS as compared to SUP‐NI. Next, IL‐6 but not IL‐5, IL‐10, IL‐17, IFN‐γ or TNF‐α reduced VIP expression in the ENS. Finally, in CD, SUP‐I incubated with anti‐IL‐6 antibody increased VIP expression as compared to SUP‐I alone.
Conclusions & Inferences
Mucosal soluble factors from IBD induce VIP neuroplastic changes in the ENS. IL‐6 was identified as a putative soluble factor responsible in part for changes in VIP expression in CD.
Mucosal soluble factors from IBD induce VIP neuroplastic changes in the ENS. IL‐6 is a putative soluble factor responsible in part for changes in VIP expression in CD.
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