Search Results for: Gestione della malattia di Crohn

Dall’inizio dell’anno sono 11 i morti confermati per la malattia

Da documentazione e trasparenza alla gestione del rischio

Ha una severa malattia mitocondriale, il papà è al fronte

The debate on the necessity of follow-up biopsy in coeliac disease has been ongoing for decades. The follow-up biopsy was dropped largely to reduce the burden of diagnosis and management in children. However, with the appreciation that coeliac disease can present in adulthood and is often associated with complications pertinent to the adult disease, it inherently is a more chronic inflammatory disorder in adults where healing is neither rapid nor assured—and in some circumstances, even frequent. The management of other classic chronic inflammatory gastrointstinal disorders, particularly Crohn’s disease and ulcerative colitis, has slowly evolved to now treating inflammation to achieve remission both defined by endoscopy and histology. However, in adult coeliac disease, we have largely eshued that management step. Is this lack of attention due to a lack of recognition of the importance of healing in coeliac disease? Decidedly not. Many guidelines attest to the importance of achieving healing…

Fistulising perianal disease is one of the common presentations in Crohn’s disease (CD).1 Between 12% and 41% of patients with CD develop perianal complications of fistulising disease or abscesses.2 Whereas disease susceptibility in complex and multifactorial CD has been associated with over hundred genetic loci allowing insight into the pathophysiology, the genetic basis and functional mechanisms of disease subphenotypes such as fistulising perianal disease are less well understood and better mechanistic and therapeutic insights are needed.3 Under homeostatic conditions, tissue resident intestinal macrophages with high phagocytic activity ingest and eliminate translocating bacteria in the intestine without eliciting an inflammatory immune response.4 In inflammatory bowel disease (IBD), multiple factors including intestinal dysbiosis and possibly damaged epithelial barrier due to ulceration and inflammatory conditions can cause a significantly higher influx of translocating and potentially invading bacteria. To prevent systemic spreading of bacteria and…

Mucosal healing on endoscopy has emerged as a key prognostic parameter in the management of patients with IBD (Crohn’s disease, ulcerative colitis/UC) and can predict sustained clinical remission and resection-free survival. The structural basis for this type of mucosal healing is a progressive resolution of intestinal inflammation with associated healing of ulcers and improved epithelial barrier function. However, in some cases with mucosal healing on endoscopy, evidence of histological activity in mucosal biopsies has been observed. Subsequently, in UC, a second, deeper type of mucosal healing, denoted histological healing, was defined which requires the absence of active inflammation in mucosal biopsies. Both levels of mucosal healing should be considered as initial events in the resolution of gut inflammation in IBD rather than as indicators of complete transmural healing. In this review, the effects of anti-inflammatory, biological or immunosuppressive agents as well as small molecules on mucosal healing in clinical studies are highlighted. In addition, we focus on the implications of mucosal healing for clinical management of patients with IBD. Moreover, emerging techniques for the analysis of mucosal healing as well as potentially deeper levels of mucosal healing such as transmural healing and functional barrier healing of the mucosa are discussed. Although none of these new levels of healing indicate a definitive cure of the diseases, they make an important contribution to the assessment of patients’ prognosis. The ultimate level of healing in IBD would be a resolution of all aspects of intestinal and extraintestinal inflammation (complete healing).

Objective
Perianal Crohn’s disease (pCD) occurs in up to 40% of patients with CD and is associated with poor quality of life, limited treatment responses and poorly understood aetiology. We performed a genetic association study comparing CD subjects with and without perianal disease and subsequently performed functional follow-up studies for a pCD associated SNP in Complement Factor B (CFB).

Design
Immunochip-based meta-analysis on 4056 pCD and 11 088 patients with CD from three independent cohorts was performed. Serological and clinical variables were analysed by regression analyses. Risk allele of rs4151651 was introduced into human CFB plasmid by site-directed mutagenesis. Binding of recombinant G252 or S252 CFB to C3b and its cleavage was determined in cell-free assays. Macrophage phagocytosis in presence of recombinant CFB or serum from CFB risk, or protective CD or healthy subjects was assessed by flow cytometry.

Results
Perianal complications were associated with colonic involvement, OmpC and ASCA serology, and serology quartile sum score. We identified a genetic association for pCD (rs4151651), a non-synonymous SNP (G252S) in CFB, in all three cohorts. Recombinant S252 CFB had reduced binding to C3b, its cleavage was impaired, and complement-driven phagocytosis and cytokine secretion were reduced compared with G252 CFB. Serine 252 generates a de novo glycosylation site in CFB. Serum from homozygous risk patients displayed significantly decreased macrophage phagocytosis compared with non-risk serum.

Conclusion
pCD-associated rs4151651 in CFB is a loss-of-function mutation that impairs its cleavage, activation of alternative complement pathway, and pathogen phagocytosis thus implicating the alternative complement pathway and CFB in pCD aetiology.