[Show abstract][Hide abstract] ABSTRACT: Background
Endoscopic activity has become a therapeutic endpoint in inflammatory bowel disease. Aim of this study was to evaluate inter-observer agreement for endoscopic scores in a real-life setting.
14 gastroenterologists with experience in inflammatory bowel disease care and endoscopic scoring reviewed videos of ulcerative colitis (n = 13) and postoperative (n = 10) and luminal (n = 8) Crohn's disease. The Mayo subscore for ulcerative colitis, Rutgeerts score for postoperative Crohn's disease, Crohn's disease endoscopic index of severity (CDEIS), and the simple endoscopic score-Crohn's disease (SES-CD) for luminal Crohn's disease were calculated. A subset of five endoscopic clips were assessed by 30 general gastroenterologists without specific experience in endoscopic scores. Kappa statistics and intraclass correlation coefficients were used to measure agreement.
Mayo subscore agreement was suboptimal: kappas were 0.53 (95% confidence interval 0.47–0.56) and 0.71 (0.67–0.76) for the two groups. Rutgeerts score agreement was fair: kappas were 0.57 (0.51–0.65) and 0.67 (0.60–0.72). Agreements for CDEIS and SES-CD were good: intraclass correlation coefficients for the two groups were 0.83 (0.54–1.00) and 0.67 (0.36–0.97) for CDEIS and 0.93 (0.76–1.00) and 0.68 (0.35–0.97) for SES-CD, respectively.
The reproducibility of endoscopic scores in inflammatory bowel disease remains suboptimal, which could potentially have major effects on therapeutic choices.
[Show abstract][Hide abstract] ABSTRACT: Crohn's disease (CD) represents a highly debilitating disease of difficult diagnosis and increasing incidence. Serum protein profiling of early stage Crohn's disease (ES) CD was investigated in order to improve the comprehension of the very early pathologic mechanisms and to support the difficult diagnostic procedures currently available. Inflammatory proteins and complement 3 chain C (C3c) were over-represented during ES CD, clusterin, retinol binding protein, α1-microglobulin and transthyretin were under-represented. A C3c isoform was found to be present only during ES CD. By now, lack of specific antibodies to detect isoforms made it impossible to perform alternative validation.
EuPA Open Proteomics 06/2014; 3. DOI:10.1016/j.euprot.2014.02.010
[Show abstract][Hide abstract] ABSTRACT: ABO encodes a glycosyltranferase which determines the major human histo-blood group. The FUT2 fucosyltransferase allows expression of ABO antigens on the gastrointestinal mucosa and in bodily secretions (secretor phenotype). A nonsense allele in FUT2 represents a susceptibility variant for Crohn's disease, and both the secretor and ABO blood group status affect the composition of the gut microbiota. Thus, we evaluated if variants in ABO might represent good candidates as Crohn's disease susceptibility loci.
We recruited two case-control cohorts, from Italy (n=1301) and Belgium (n=2331). Subjects were genotyped for one SNP in FUT2 and two variants in ABO.
No effect on Crohn's disease risk was detected for ABO variants, whereas an association was observed between the FUT2 polymorphism and Crohn's disease susceptibility in the Belgian sample, but not in the Italian cohort. The effect of histo-blood groups was evaluated using group O as the reference. Most non-O groups had odds ratios (ORs) higher than 1 in both cohorts, and combined analysis of the two samples indicated a predisposing effect for the A and B groups (OR=1.17, 95% CI: 1.02-1.32 and OR=1.33, 95% CI: 1.09-1.58, respectively). In Crohn's disease patients, the non-O blood group and the non-secretor status were associated with higher risk of developing a stricturing or penetrating disease.
ABO histo-blood group might confer susceptibility to Crohn's disease and modulate disease severity.
Journal of Crohn s and Colitis 11/2013; 8(6). DOI:10.1016/j.crohns.2013.10.014 · 6.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Previous studies indicated that a few risk variants for autoimmune diseases are subject to pathogen-driven selection. Nonetheless, the proportion of risk loci that has been targeted by pathogens, and the type of infectious agent(s) which exerted the strongest pressure remain to be evaluated. We assessed whether different pathogens exerted a pressure on known Crohn's disease (CD) risk variants, and demonstrate that these SNPs are preferential targets of protozoa-driven selection (p=0.008). In particular, 19% of SNPs associated with CD have been subject to protozoa-driven selective pressure. Analysis of p values from GWASs and meta-analyses indicated that protozoan-selected SNPs display significantly stronger association with CD compared to non-selected variants. This same behavior was not observed for GWASs of other autoimmune diseases. Thus, we integrated selection signatures and meta-analysis results to prioritize 5 genic SNPs for replication in an Italian cohort. Three SNPs were significantly associated with CD risk and combination with meta-analysis results yielded p values < 4x10(-6). The bona fide risk alleles are located in ARHGEF2, an interactor of NOD2, NSF, a gene involved in autophagy, and HEBP1, encoding a possible mediator of inflammation. Pathway analysis indicated that ARHGEF2 and NSF participate in a molecular network which also contains VAMP3 (previously associated to CD), and is centered around miR-31 (known to be disregulated in CD). Thus, we show that protozoa-driven selective pressure had a major role in shaping predisposition to CD. We next used this information for the identification of three bona fide novel susceptibility loci.
[Show abstract][Hide abstract] ABSTRACT: The introduction of anti-TNF agents for the treatment of rheumatoid arthritis (RA), Crohn's disease (CD) or spondyloarthritis (SpA) revolutionised the therapeutic approach to patients with active disease who failed to respond to conventional therapy. However, patients with RA, CD and SpA who are treated with selective tumour necrosis factor (TNF) inhibitors may develop autoantibodies such as antinuclear antibodies (ANAs) and anti-double-stranded DNA (anti-dsDNA) antibodies. Anti-phospholipid antibodies, which are mainly detected by means of anti-cardiolipin assays, have also been found in RA patients receiving TNF blockers. There have been a number of reports of the development of anti-drug antibodies, of which those against infliximab can interfere with the pharmacokinetics of a drug and therefore with its effects. They may also cause acute and delayed infusion and injection site reactions. The onset of autoimmune diseases during biological treatment is a rare event, but it needs to be promptly recognised in order to plan appropriate patient management. Immunosuppressive drug addiction can reduce the induction of anti-TNF antibodies.
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Recent insight into the pathogenesis of ulcerative colitis have led to the development of new treatment options. A better understanding of IBD pathophysiology has progressively led to a more frequent use of immunosuppressants and biologics.
The use of the conventional immunomodulators, such as azathioprine, 6-mercaptopurine, methotrexate, cyclosporine and tacrolimus, and anti-TNF-α agents, such as infliximab and adalimumab, in the treatment of ulcerative colitis are reviewed. Moreover, the ongoing studies evaluating the efficacy of emerging immunosuppressants in treating patients with ulcerative colitis are discussed. An effort is made to explore some critical areas in which early and more diffuse use of these agents may be advocated.
Ulcerative colitis is a chronic condition mainly affecting young people in their more productive age, and determining high indirect costs to the patient and to society. Thus, there is a need for optimizing and renewing our traditional therapeutic approach to UC, and new therapies beyond conventional treatment options possibly aiming to change the poor clinical course of many patients with ulcerative colitis. Keeping in mind this potentially new therapeutic scenario, there are some critical areas in which early and more diffuse use of conventional and emerging new immunomodulators is advocated.
[Show abstract][Hide abstract] ABSTRACT: The ERAP1 gene encodes an aminopeptidase involved in antigen processing. A functional polymorphism in the gene (rs30187, Arg528Lys) associates with susceptibility to ankylosying spondylitis (AS), whereas a SNP in the interacting ERAP2 gene increases susceptibility to another inflammatory autoimmune disorder, Crohn's disease (CD). We analysed rs30187 in 572 Italian patients with CD and in 517 subjects suffering from multiple sclerosis (MS); for each cohort, an independent sex- and age-matched control group was genotyped. The frequency of the 528Arg allele was significantly higher in both disease cohorts compared to the respective control population (for CD, OR = 1.20 95%CI: 1.01-1.43, p = 0.036; for RRMS, OR = 1.26; 95%CI: 1.04-1.51, p = 0.01). Meta-analysis with the Wellcome Trust Cases Control Consortium GWAS data confirmed the association with MS (p(meta) = 0.005), but not with CD. In AS, the rs30187 variant has a predisposing effect only in an HLA-B27 allelic background. It remains to be evaluated whether interaction between ERAP1 and distinct HLA class I alleles also affects the predisposition to MS, and explains the failure to provide definitive evidence for a role of rs30187 in CD. Results herein support the emerging concept that a subset of master-regulatory genes underlay the pathogenesis of autoimmunity.
PLoS ONE 01/2012; 7(1):e29931. DOI:10.1371/journal.pone.0029931 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Autologous haematopoietic stem cells transplantation (HSCT) has been shown to be effective in refractory Crohn's disease.
We analysed the effects of HSCT on the immune response of patients treated for moderate-severe Crohn's disease, refractory or intolerant to multiple drugs.
Unselected peripheral blood stem cells were collected after mobilisation with cyclophosphamide (CTX) and G-CSF. The conditioning regimen included CTX and rabbit antithymocyte globulin. Blood samples for immunological analyses were collected at baseline, after mobilisation, and 3, 6 and 12 months after transplantation. Immunological analyses evaluated: (1) CD4(+)/CD25(high+)/FoxP3(+) regulatory T cells (T-regs); (2) Toll-like receptor 2-(TLR2) and TRL4-expressing monocytes (CD14(+) cells); (3) IL-12, IL-10, TNF-alpha-production by mitogen-stimulated CD14(+) cells and IFN-gamma production by CD4(+) T cells. Immunological results were compared with healthy donors and associated with clinical and endoscopic response during 12 months of follow-up.
Overall, T-regs increased, whilst TLR4-expressing cells, as well as TNF-alpha and IL-10, all higher than healthy donors at baseline, significantly decreased after transplantation. Full responders at T(3) had higher T-regs and lower IFN-gamma and IL12. T-regs decreased and IL12 and TLR2 increased in the only relapsed patient.
HSCT can induce and maintain clinical and endoscopic remission in refractory Crohn's disease, which is associated with immunomodulation.
[Show abstract][Hide abstract] ABSTRACT: The human RAC2 gene encodes a small GTP-binding protein with a pivotal role in immune activation and in the induction of peripheral immune tolerance through restimulation-induced cell death (RICD). Different human pathogens target the protein product of RAC2, suggesting that the gene may be subject to natural selection, and that variants in RAC2 may affect immunological phenotypes in humans. We scanned the genomic region encompassing the entire transcription unit for the presence of putative noncoding regulatory elements conserved across mammals. This information was used to select two RAC2 gene regions and analyze their intraspecific genetic diversity. Results suggest that a region covering the 3' untranslated region has been a target of multiallelic balancing selection (or diversifying selection), and three major RAC2 haplogroups occur in human populations. Haplotypes belonging to one of these clades are associated with increased susceptibility to multiple sclerosis (P = 0.022) and earlier onset of disease symptoms (P = 0.025). This same haplogroup is significantly more common in patients with Crohn's disease compared with healthy controls (P = 0.048). These data reinforce recent evidences that susceptibility alleles/haplotypes are shared among multiple autoimmune disorders and support a causal "role for RAC2" variants in the pathogenesis of autoimmune diseases. Other genes with a role in RICD have previously been associated with autoimmunity in humans, suggesting that this pathway and RAC2 may represent novel therapeutic targets in autoimmune disorders.