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The chronic inflammation of Crohn's disease is caused, at least in part, by repression of TGF-β1 signaling, which is caused by high levels of SMAD7. This trial shows that mongersen, an antisense inhibitor of SMAD7 mRNA, induces disease remission in some persons. Crohn’s disease is a chronic inflammatory illness that primarily affects the terminal ileum and right colon. Crohn’s disease–related inflammation is segmental and transmural, leading to various degrees of tissue damage. 1 At disease onset, most patients have inflammatory lesions, which become predominantly strictures or penetrating lesions over time. 2 , 3 Mucosal healing can be promoted with the use of immunosuppressive drugs and anti–tumor necrosis factor α (TNF- α ) antibodies; however, more than one third of patients do not have a response to these therapies. The efficacy of these drugs may also diminish over time, and they can increase a patient’s risk . . .

To evaluate the efficacy and safety of purine analogs (azathioprine, 6-mercaptopurine (6-MP)) in the prevention of postoperative recurrence in Crohn's disease (CD). We searched MEDLINE, the Cochrane Library, and EMBASE. The primary end points, clinical and endoscopic recurrence at 1 and 2 years, and safety were analyzed by the methods of Peto and Der Simonian and Laird. Four controlled trials enrolled 433 patients and compared azathioprine (n=3) or (6-MP) (n=1) with control arms (placebo with or without antibiotic induction therapy or mesalamine). In the overall analysis, purine analogs were more effective than control arms in preventing clinical recurrence at 1 year (mean difference, 95% confidence interval (CI): 8, 1-15%, P=0.021, number needed to treat (NNT)=13) and 2 years (mean difference, 95% CI: 13%, 2-24%, P=0.018, NNT=8). In sensitivity analyses, the efficacy of purine analogs was superior to that of placebo for the prevention of clinical and endoscopic recurrence at 1 year (mean differences, 95% CI: 13, 1.8-25%, P=0.025, NNT=7, and 23%, 9-37%, P=0.0016, NNT=4, respectively). At 1 year, in the overall analysis, purine analogs were more effective than control arms were in preventing severe (i2-4) endoscopic recurrence (mean difference, CI 95%: 15, 1.8-29%, P=0.026, NNT=7), but they were not effective in the prevention of very severe (i3-4) recurrence. The rate of adverse events leading to drug withdrawal was higher in thiopurine-treated patients than in control arms (17.2 vs. 9.8%, respectively, P=0.021). Purine analogs are more effective than placebo in preventing both clinical and endoscopic postoperative recurrence in CD, but they are associated with a higher rate of adverse events leading to drug withdrawal.

Human papillomavirus (HPV) is a recognized oncogenic agent in several epithelial malignancies, though its role in esophageal squamous lesions remains unclear. Esophageal squamous papilloma and papillomatosis are rare, often benign lesions, but increasing evidence suggests possible associations with high-risk HPV genotypes and a non-negligible risk of dysplasia and malignant transformation. This narrative review summarizes current evidence on epidemiology, clinical features, histopathology, and diagnostic approaches, emphasizing advanced endoscopic imaging techniques that improve lesion detection and characterization. Management relies primarily on complete endoscopic resection with histological and virological evaluation. While small, non-dysplastic solitary lesions may not require routine surveillance, multifocal or high-risk HPV-positive cases warrant closer follow-up. Standardized HPV testing and long-term prospective studies are needed to better define the oncogenic potential and inform surveillance and treatment strategies.

Mechanisms by which mucosal regeneration is abrogated in inflammatory bowel disease (IBD) are still under investigation, and a role for an intestinal stem cell (ISC) defect is now emerging. Herein, we report an abnormal ISC death that occurs in Crohn's disease, which exacerbates colitis, limits ISC-dependent mucosal repair, and is controlled through the death factor Transmembrane protein 219 (TMEM219). Large alterations in TMEM219 expression were observed in patients with Crohn's disease, particularly in those with active disease and/or those who were nonresponders to conventional therapy, confirming that TMEM219 signaling is abnormally activated and leads to failure of the mucosal regenerative response. Mechanistic studies revealed a proapoptotic TMEM219-mediated molecular signature in Crohn's disease, which associates with Caspase-8 activation and ISC death. Pharmacological blockade of the IGFBP3/TMEM219 binding/signal with the recombinant protein ecto-TMEM219 restored the self-renewal abilities of miniguts generated from patients with Crohn's disease in vitro and ameliorated DSS-induced and T cell-mediated colitis in vivo, ultimately leading to mucosal healing. Genetic tissue-specific deletion of TMEM219 in ISCs in newly generated TMEM219fl/flLGR5cre mice revived their mucosal regenerative abilities both in vitro and in vivo. Our findings demonstrate that a TMEM219-dependent ISC death exacerbates colitis and that TMEM219 blockade reestablishes intestinal self-renewal properties in IBD.

Mucosal healing has been proposed as an important sign of the efficacy of medical treatment of inflammatory bowel disease; however, direct evidence in ulcerative colitis (UC) is scarce. We evaluated the usefulness of colonoscopy and bowel ultrasound (US) as indexes of response to short-term therapy and as predictors of subsequent outcome in UC. A total of 83 patients with moderate-to-severe UC were recruited; endoscopic and US severity was graded 0-3 at entry according to validated scores. Of the recruited patients, 74, who were clinically responsive to steroids, were followed up with repeated colonoscopy and bowel US at 3, 9, and 15 months from recruitment. Concordance between clinical, endoscopic, and US scores at various visits was determined by kappa statistics. Multiple unconditional logistic regression models were used to assess the predictivity of clinical, endoscopic, and US scores measured at 3 and 9 months on the development of endoscopic UC relapse within 15 months. A variable concordance was found over time between endoscopic and clinical score (weighted kappa between 0.38 and 0.95), with high and consistent concordance between endoscopic and US scores (weighted kappa between 0.76 and 0.90). On logistic regression analysis, moderate-to-severe endoscopic and US scores at 3 months were associated with a high risk of endoscopic activity at 15 months (odds ratio (OR): 5.2; 95% confidence interval (CI): 1.6-17.6 and OR: 9.1; 95% CI: 2.5-33.5, respectively). Bowel US may be used as a surrogate of colonoscopy in assessing the short-term response of severe forms of UC to therapy. Both US score and endoscopic score after 3 months of steroid therapy predict outcome of disease at 15 months.

Patients with Immune-Mediated Inflammatory Diseases (IMIDs) are known to have an elevated risk of developing cancer, but the exact causative factors remain subject to ongoing debate. This narrative review aims to present the available evidence concerning the intricate relationship between these two conditions. Environmental influences and genetic predisposition lead to a dysregulated immune response resulting in chronic inflammation, which is crucial in the pathogenesis of IMIDs and oncogenic processes. Mechanisms such as the inflammatory microenvironment, aberrant intercellular communication due to abnormal cytokine levels, excessive reparative responses, and pathological angiogenesis are involved. The chronic immunosuppression resulting from IMIDs treatments further adds to the complexity of the pathogenic scenario. In conclusion, this review highlights critical gaps in the current literature, suggesting potential avenues for future research. The intricate interplay between IMIDs and cancer necessitates more investigation to deepen our understanding and improve patient management.

The evaluation of the degree of inflammation and fibrosis, intrinsic elements in intestinal wall damage of Crohn’s disease, is essential to individuate the extent of the lesions and the presence of strictures. This information will contribute to the choice of the appropriate therapeutic approach, the prediction of the response to therapy and the course of the disease. The accurate evaluation of the extent and severity of inflammation and/or fibrosis in Crohn’s disease currently requires histopathological analysis of the intestinal wall. However, in clinical practice and research, transmural assessment of the intestinal wall with cross sectional imaging is increasingly used for this purpose. The B-mode ultrasonograhic characteristics of the intestinal wall, the assessment of its vascularization by color Doppler and I.V. contrast agents, and the evaluation of the mechanical and elastic properties by sonoelastography, may provide useful and accurate information on the severity and extent of inflammation and intestinal fibrosis in Crohn’s disease. The purpose of this review is to provide an update on current sonographic methods to discriminate inflammation and fibrosis in Crohn’s disease.

To evaluate the ability of intestinal ultrasound (IUS) in discriminating symptomatic uncomplicated diverticular disease (SUDD) among patients with abdominal symptoms including irritable bowel syndrome (IBS). This observational, prospective study included consecutive patients classified into the following categories: (i) SUDD; (ii) IBS; (iii) unclassifiable abdominal symptoms; and (iv) controls, including asymptomatic healthy subjects and diverticulosis. The IUS evaluation of the sigmoid: assessed the presence of diverticula, thickness of the muscularis propria, and IUS-evoked pain, namely the intensity of pain evoked by compression with the ultrasound probe on sigmoid colon compared with an area of the left lower abdominal quadrant without underlying sigmoid colon. We enrolled 40 patients with SUDD, 20 patients with IBS, 28 patients with unclassifiable abdominal symptoms, 10 healthy controls, and 20 patients with diverticulosis. Patients with SUDD displayed significantly ( P < 0.001) greater muscle thickness (2.25 ± 0.73 mm) compared with patients with IBS (1.66 ± 0.32 mm), patients with unclassifiable abdominal pain, and healthy subjects, but comparable with that of patients with diverticulosis (2.35 ± 0.71 mm). Patients with SUDD showed a greater (not significant) differential pain score than other patients. There was a significant correlation between the thickness of the muscularis propria and the differential pain score only for patients with SUDD ( r = 0.460; P : 0.01). Sigmoid diverticula were detected by colonoscopy in 40 patients (42.4%) and by IUS with a sensitivity of 96.0% and a specificity of 98.5%. IUS could represent a useful diagnostic tool for SUDD, potentially useful in characterizing the disease and appropriately address the therapeutic approach.

Since March 2020, the outbreak of Sars-CoV-2 pandemic has changed medical practice and daily routine around the world. Huge efforts from pharmacological industries have led to the development of COVID-19 vaccines. In particular two mRNA vaccines, namely the BNT162b2 (Pfizer-BioNTech) and the mRNA-1273 (Moderna), and a viral-vectored vaccine, i.e. ChAdOx1 nCoV-19 (AstraZeneca), have recently been approved in Europe. Clinical trials on these vaccines have been published on the general population showing a high efficacy with minor adverse events. However, specific data about the efficacy and safety of these vaccines in patients with immune-mediated inflammatory diseases (IMIDs) are still lacking. Moreover, the limited availability of these vaccines requires prioritizing some vulnerable categories of patients compared to others. In this position paper, we propose the point of view about the management of COVID-19 vaccination from Italian experts on IMIDs and the identification of high-risk groups according to the different diseases and their chronic therapy.

The etiology of inflammatory bowel disease (IBD) has not yet been clarified and immunosuppressive agents which nonspecifically reduce inflammation and immunity have been used in the conventional therapies for IBD. Evidence indicates that a dysregulation of mucosal immunity in the gut of IBD causes an overproduction of inflammatory cytokines and trafficking of effector leukocytes into the bowel, thus leading to an uncontrolled intestinal inflammation. Under normal situations, the intestinal mucosa is in a state of \"controlled\" inflammation regulated by a delicate balance of proinflammatory (tumor necrosis factor [TNF-alpha], interferon-gamma [IFN-gamma], interleukin-1 [IL-1], IL-6, IL-12 and anti-inflammatory cytokines IL-4, IL-10, IL-11). The mucosal immune system is the central effector of intestinal inflammation and injury, with cytokines playing a central role in modulating inflammation. Cytokines may therefore be a logical target for inflammatory bowel disease therapy using specific cytokine inhibitors. Biotechnology agents targeted against TNF, leukocyte adhesion, Th1 polarization, T cell activation, nuclear factor-kappaB (NF-kappaB), and other miscellaneous therapies are being evaluated as potential therapies for the treatment of inflammatory bowel disease. In this context, infliximab and adalimumab are currently the only biologic agents approved in Europe for the treatment of inflammatory Crohn's disease. Other anti-TNF biologic agents have emerged, including CDP571, certolizumab pegol, etanercept, onercept. However, ongoing research continues to generate new biologic agents targeted at specific pathogenic mechanism involved in the inflammatory process. Lymphocyte-endothelial interactions mediated by adhesion molecules are important in leukocyte migration and recruitment to sites of inflammation, and selective blockade of these adhesion molecules is a novel and promising strategy to treat Crohn's disease. Therapeutics agents to inhibit leukocyte trafficking include natalizumab (approved for use in Crohn's disease in USA), MLN-02, and ISIS 2302. Other agents being investigated for the treatment of Crohn's disease include inhibitors of T cell activation, proinflammatory cytokine receptors, Th1 polarization, growth hormone, and growth factors. Agents being investigated for treatment of ulcerative colitis include many of those mentioned above. Controlled clinical trials are currently being conducted, exploring the safety and efficacy of old and new biologic agents, and the search certainly will open new and exciting perspective on the development of therapies for inflammatory bowel disease. A review is made of the main areas of research exploring the mechanisms associated with the pathogenesis of IBD, providing advances in the agents currently in use, and identifying a host of new therapeutic biologic targets.