A nationwide, multi-center, retrospective study of symptomatic small bowel stricture in patients with Crohn\u27s disease.

BACKGROUND:Small bowel stricture is one of the most common complications in patients with Crohn\u27s disease (CD). Endoscopic balloon dilatation (EBD) is a minimally invasive treatment intended to avoid surgery; however, whether EBD prevents subsequent surgery remains unclear. We aimed to reveal the factors contributing to surgery in patients with small bowel stricture and the factors associated with subsequent surgery after initial EBD.METHODS:Data were retrospectively collected from surgically untreated CD patients who developed symptomatic small bowel stricture after 2008 when the use of balloon-assisted enteroscopy and maintenance therapy with anti-tumor necrosis factor (TNF) became available.RESULTS:A total of 305 cases from 32 tertiary referral centers were enrolled. Cumulative surgery-free survival was 74.0% at 1 year, 54.4% at 5 years, and 44.3% at 10 years. The factors associated with avoiding surgery were non-stricturing, non-penetrating disease at onset, mild severity of symptoms, successful EBD, stricture length < 2 cm, and immunomodulator or anti-TNF added after onset of obstructive symptoms. In 95 cases with successful initial EBD, longer EBD interval was associated with lower risk of surgery. Receiver operating characteristic analysis revealed that an EBD interval of ≤ 446 days predicted subsequent surgery, and the proportion of smokers was significantly high in patients who required frequent dilatation.CONCLUSIONS:In CD patients with symptomatic small bowel stricture, addition of immunomodulator or anti-TNF and smoking cessation may improve the outcome of symptomatic small bowel stricture, by avoiding frequent EBD and subsequent surgery after initial EBD

Adrenomedullin: A Novel Therapeutic for the Treatment of Inflammatory Bowel Disease

Adrenomedullin (AM) is a bioactive peptide with various physiological functions, including vasodilation, angiogenesis, anti-inflammation, organ protection, and tissue repair. AM suppresses inflammatory cytokine production in the intestinal mucosa, improves vascular and lymphatic regeneration and function, mucosal epithelial repair, and immune function in the intestinal bacteria of animal models with intestinal inflammation. We have been promoting translational research to develop novel therapeutic agents for inflammatory bowel disease (IBD) using AM and have started clinical research for IBD patients since 2010. A multicenter clinical trial is currently underway in Japan for patients with refractory ulcerative colitis and Crohn’s disease. Moreover, since current AM administration is limited to continuous intravenous infusion, the development of a subcutaneous formulation using long-acting AM is underway for outpatient treatment

20 kDa PEGylated Adrenomedullin as a New Therapeutic Candidate for Inflammatory Bowel Disease

Human adrenomedullin (AM), a hypotensive peptide, also has anti-colitis activity. We prepared a polyethylene glycol (PEG) ylated form of AM through the conjugation of PEG-AM (1&ndash;15) and AM (15&ndash;52). Highly pure monomeric 20 kDa PEG-AM (20kPEG-AM) stimulated cyclic adenosine monophosphate production in HEK-293 cells stably expressing the type 1 AM receptor in a dose-dependent manner. The half-life of 20kPEG-AM was 7.4 h following subcutaneous administration in mice. We assessed the anti-colitis effect of subcutaneous 20kPEG-AM administration in the dextran sodium sulfate murine colitis model. Single and double subcutaneous injection of 20kPEG-AM significantly reduced total inflammation scores. These results suggest that 20kPEG-AM is a promising therapeutic candidate for the treatment of human inflammatory bowel diseases

20 kDa PEGylated Adrenomedullin as a New Therapeutic Candidate for Inflammatory Bowel Disease

Human adrenomedullin (AM), a hypotensive peptide, also has anti-colitis activity. We prepared a polyethylene glycol (PEG) ylated form of AM through the conjugation of PEG-AM (1–15) and AM (15–52). Highly pure monomeric 20 kDa PEG-AM (20kPEG-AM) stimulated cyclic adenosine monophosphate production in HEK-293 cells stably expressing the type 1 AM receptor in a dose-dependent manner. The half-life of 20kPEG-AM was 7.4 h following subcutaneous administration in mice. We assessed the anti-colitis effect of subcutaneous 20kPEG-AM administration in the dextran sodium sulfate murine colitis model. Single and double subcutaneous injection of 20kPEG-AM significantly reduced total inflammation scores. These results suggest that 20kPEG-AM is a promising therapeutic candidate for the treatment of human inflammatory bowel diseases.Citation: Miki, G.; Kuroishi, N.; Tokashiki, M.; Nagata, S.; Tamura, M.; Yoshiya, T.; Yoshizawa-Kumagaye, K.; Ashizuka, S.; Kato, J.; Yamasaki, M.; et al. 20 kDa PEGylated Adrenomedullin as a New Therapeutic Candidate for Inflammatory Bowel Disease. Gastrointest. Disord. 2020, 2, 366-377. https://doi.org/10.3390/gidisord204003