Introduction: Currently, mucosal healing is considered as a composite treatment end-point in inflammatory bowel disease (IBD) since it has been demonstrated to improve disease-related outcomes. The ...definition of mucosal healing has evolved and current evidence suggests that in addition to endoscopic healing the achievement of histological remission (HR) represents a potential novel target in the management of IBD in relation to better long-term disease outcomes.
Areas covered: We aimed to review the current literature on HR in ulcerative colitis and discuss its limitations and advantages when adopting this potential new target as an ultimate treatment outcome in clinical trials and routine clinical practice.
Expert opinion: HR is achievable in UC with different rates in conventional therapies, biological and novel drugs. Targeting HR in UC lowers the risk of hospitalizations, colectomy, and colorectal cancer. HR occurs later than endoscopic remission, longer treatment courses are associated with higher HR assessment. This might imply modifying monitoring time schedules and algorithms. Prospective data are needed to support histological healing as a new treatment target in UC.
Introduction: Ulcerative colitis (UC) is a chronic relapsing disorder of the colonic tract. Dysregulated innate and adaptive immune pathways contribute to intestinal inflammation in IBD, and ...cytokines, including IL-12 and IL-23, play a key role. The blockade of both IL-12 and IL-23 may have an impact on different pathways of inflammation and could be effective for the treatment of inflammatory bowel diseases.
Ustekinumab is a fully human IgG1κ monoclonal antibody which binds to the shared p40 protein subunit of IL-12 and −23. It is currently approved for several immune-mediated diseases such as moderate to severe plaque psoriasis, psoriatic arthritis, and Crohn's disease, and has shown promising results in UC.
Areas covered: A review of the literature was performed to understand several aspects including the role of IL-12 and −23 in UC, the potential therapeutic role of ustekinumab in inflammatory bowel disease, and the positioning of ustekinumab in the therapeutic algorithm of UC, based on extrapolated data from available randomized clinical trials.
Expert opinion: Ustekinumab is effective and safe in UC, and shows potential advantages compared to other drugs in moderate-to-severe UC.
Bile acids (BAs) are the end product of cholesterol catabolism. Their synthesis is regulated by the nuclear receptor farnesoid X receptor, also involved in the control of their enterohepatic ...circulation. Inflammatory bowel diseases (IBD), which include Crohn's disease (CD) and ulcerative colitis (UC), are multifactorial diseases characterized by diarrhea. The pathogenesis of diarrhea in IBD is still debated. The most important factor is the inflammatory process of the intestinal wall, causing alterations of solute and water absorption/secretion, deterioration of epithelial cell integrity, disruption of the intestinal microflora homeostasis, and impairment of specific transport mechanisms within the gut (including that of BAs). In this review, we summarize the current state of the art in this area and we critically evaluate the alterations of BA metabolism in patients with CD and UC.
Introduction: The Notch-1 signaling pathway is responsible for homeostatic tight junction (TJ) expression in vitro and maintenance of barrier function. Lamina propria lymphocytes (LPLs) promote ...barrier function in vivo in the RAG1-adoptive transfer model of colitis, putatively due to the Notch-1 pathway. Notch-1 activation is increased in Crohn's disease epithelia compared to normal or ulcerative colitis. We sought to determine the role of epithelial Notch-1 in the lympho-epithelial crosstalk in health and disease. Methods: Wild type (WT) mice were treated with Notch-1 or scrambled siRNA with or without a 3 % DSS regimen. We studied the impact of in vivo Notch-1 knock-down (KD) on epithelial differentiation, barrier function and mucosal immune response. Human PBMCs were stimulated with supernatants from the Notch-1 KD Caco-2 cells in order to assess the immuno-modulatory role of epithelial Notch-1 in vitro. Results: Notch-1 and claudin-5 expression was decreased in Notch-1 siRNA treated animals, and permeability was increased. These mice were more susceptible to DSS colitis and showed decreased LP and MLN FoxP3+ cells, decreased colonic chemokine mRNA expression and effector T cell cytokine secretion. Notch-1 KD Caco-2 cells had lower basal cytokine expression and dampened response to TNFalpha. The supernatant from these cells induced lower levels of FoxP3 expression in CD4+ T cells as well as IL-6, -10 and IFNgamma secretion from stimulated PBMCs. Conclusion: We identified that epithelial Notch-1 is required for appropriate activation of intestinal epithelial cells at steady state and during inflammation. Epithelial activation under the control of Notch-1 expression modulates chemokine and cytokine secretion, and FoxP3 and effector T cell responses. We showed that epithelial Notch-1 controls the immune function of the epithelium, which, in turn, elicits T cell responses. Our findings highlight an indispensable role for Notch-1 mediated signaling in the intricate epithelial-immune crosstalk, and validate that epithelial Notch-1 is necessary and sufficient to support protective epithelial pro-inflammatory responses. Intestinal epithelial Notch-1 signaling shapes the underlying immune response at steady state and during inflammation. Overall, epithelial Notch-1 bridges innate and adaptive immunity in the gut.
Introduction: Biosimilars represent great potential in cost saving and re-investment opportunities in healthcare and allow patients greater access to effective mAbs. Infliximab biosimilars are ...successfully used in all indications for whom the reference product (RP) was approved.
Areas covered: In late 2018, adalimumab biosimilars will also be available in patients with inflammatory bowel disease (IBD).
ABP501, BI 695501, GP2017, and SB5 have been approved by the EMA for the same indications of the reference product (RP, Humira®). Preclinical data show high similarity between all biosimilars and the RP. Clinical data in patients with rheumatoid arthritis and psoriasis also show no differences in terms of efficacy, safety, and immunogenicity. Data in IBD patients are still lacking.
Expert opinion: Biosimilars of adalimumab appear to be clinically equivalent to the RP. Decisions based on choosing the ideal patient to receive or to be switched to a biosimilar of adalimumab, or choosing one biosimilar vs. another, or cross-switching among biosimilars remain the next challenge in the field of IBD.
Collagenous colitis (CC) is an inflammatory bowel disorder with unknown etiopathogenesis involving HLA-related immune-mediated responses and environmental and genetic risk factors. We carried out an ...array-based genetic association study in a cohort of patients with CC and investigated the common genetic basis between CC and Crohn’s disease (CD), ulcerative colitis (UC), and celiac disease.
DNA from 804 CC formalin-fixed, paraffin-embedded tissue samples was genotyped with Illumina Immunochip. Matching genotype data on control samples and CD, UC, and celiac disease cases were provided by the respective consortia. A discovery association study followed by meta-analysis with an independent cohort, polygenic risk score calculation, and cross-phenotype analyses were performed. Enrichment of regulatory expression quantitative trait loci among the CC variants was assessed in hemopoietic and intestinal cells.
Three HLA alleles (HLA-B∗08:01, HLA-DRB1∗03:01, and HLA-DQB1∗02:01), related to the ancestral haplotype 8.1, were significantly associated with increased CC risk. We also identified an independent protective effect of HLA-DRB1∗04:01 on CC risk. Polygenic risk score quantifying the risk across multiple susceptibility loci was strongly associated with CC risk. An enrichment of expression quantitative trait loci was detected among the CC-susceptibility variants in various cell types. The cross-phenotype analysis identified a complex pattern of polygenic pleiotropy between CC and other immune-mediated diseases.
In this largest genetic study of CC to date with histologically confirmed diagnosis, we strongly implicated the HLA locus and proposed potential non-HLA mechanisms in disease pathogenesis. We also detected a shared genetic risk between CC, celiac disease, CD, and UC, which supports clinical observations of comorbidity.
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