Timing of restorative proctocolectomy in patients with medically refractory ulcerative colitis: the patient's point of view.

BACKGROUND: Development of biologic agents has led to new therapeutic options for patients with refractory ulcerative colitis, and intensive medical therapy allows delay of restorative colectomy. However, the overall rate of colectomies has not changed. The decision as to timing of the operation is difficult. OBJECTIVE: Our aim was to elucidate the patients' views about the timing of their own proctocolectomy. DESIGN: This was a retrospective review of a prospectively designed database combined with a follow-up survey questionnaire. SETTINGS AND PARTICIPANTS: We included patients who underwent proctocolectomy and ileal pouch-anal anastomosis for refractory ulcerative colitis from 1999 through 2009 at our university hospital. MAIN OUTCOME MEASURES: A questionnaire was sent to patients asking whether they would have preferred to have had the operation performed earlier, later, or at the same time as it was actually done and to give the number of years or months earlier or later that they would have preferred. They were also asked to give reasons for their preference. Patients who preferred an earlier operation were compared with those satisfied with the timing regarding measures of postoperative quality of life and pouch function collected from the institution's prospective database. RESULTS: Of 84 eligible patients, 70 (83%) responded. Of these, 37 (53%) would have preferred an earlier operation; 33 patients (47%) were satisfied with the timing. No patient would have chosen a later operation. Patients who preferred an earlier operation wished it to have been a median of 2 years earlier (range, 2-120 months). The main reasons for a preferred earlier time point were postoperative improvement of stool regulation in 89% (33/37), reduction of bleedings in 84% (31/37), and relief of pain in 68% (25/37). No significant differences were observed between groups regarding postoperative quality of life or pouch function. LIMITATIONS: Limitations of the study included lack of validation and a nonsymmetrical structure of the questionnaire. CONCLUSIONS: About half of the patients of our study would have preferred to have had proctocolectomy earlier than it had been performed, mainly because of the relief of symptoms that they experienced after the operation. For patients with an emerging refractory course of ulcerative colitis, earlier restorative proctocolectomy should be considered as an alternative to further intensified medical treatment.

PECAM-1 (CD 31) mediates transendothelial leukocyte migration in experimental colitis.

Transendothelial migration of circulating leukocytes into the colonic wall is a key step in the development of the inflammatory infiltrate in inflammatory bowel disease (IBD). The platelet-endothelial cell adhesion molecule-1 PECAM-1 (CD31) is expressed in the tight junction area of endothelial cells, where it is supposed to support the transmigration process. The aim of this study was to determine the role of PECAM-1 in experimental IBD and to show whether blockade of PECAM-1 has therapeutic effects. Chronic colitis was induced in female BALB/c mice by cyclic oral administration of dextran sodium sulfate (DSS) 3% (wt/vol). Expression of PECAM-1 was visualized by immunohistochemistry. In the treatment group animals received 1 mg/kg anti-PECAM-1 (2H8) ip daily starting on day 26. On day 30 leukocyte adhesion and migration was measured during N(2)O-isoflurane anesthesia in the distal colon by intravital microscopy. Disease activity index (DAI), histology, and MPO levels were compared with healthy and diseased controls. PECAM-1 was expressed in colitic mice. Chronic DSS colitis was characterized by a marked increase in rolling, adherent, and transmigrated leukocytes compared with healthy controls. Immunoblockade of PECAM-1 reduced leukocyte transmigration significantly and also diminished leukocyte rolling and sticking in an indirect manner. It also resulted in a significantly diminished DAI and MPO levels, as well as an amelioration of the histological inflammation score. PECAM-1 plays an important role in transendothelial leukocyte migration in DSS colitis. PECAM-1 could be a novel target for antibody-based treatment in IBD.

Bosentan, an endothelin receptor antagonist, reduces leucocyte adhesion and inflammation in a murine model of inflammatory bowel disease.

BACKGROUND AND AIMS: Endothelins, a group of polyfunctional cytokines, induce the adhesion of circulating leucocytes to venous endothelium, an initial step in the pathogenesis of a cellular infiltrate in inflammatory bowel disease (IBD). The effect of bosentan, a non-selective endothelin receptor antagonist, on leucocyte adhesion and inflammation in a murine model of IBD was studied. MATERIALS AND METHODS: Thirty BALB/c mice were divided into three groups of 10 animals: untreated controls, chronic colitis [dextran sodium sulphate (DSS), 3% w/v for 30 days], and treatment with bosentan (30 mg/kg i.p. daily on days 26-30). On day 30, adherent and rolling leucocytes and the average rolling velocity were assessed by intravital microscopy. Clinical and histological activity of inflammation were assessed by the disease activity index and modified Dieleman score, respectively. STATISTICS: Kruskal-Wallis test was used, followed by Dunn's method. A value of p<0.05 was considered significant. RESULTS: Compared to healthy controls, mice treated with DSS showed pronounced clinical and histological inflammation, and a higher number of rolling and adhering leucocytes in colonic submucosal venules. Therapy with bosentan significantly reduced clinical and histological inflammation. Adherent leucocyte levels were markedly lower (1.2+/-0.3 vs 23.7+/-2.8 adherent cells per 0.01 mm2, p<0.05). The number of rolling leucocytes was lower but not significantly different. However, rolling velocity was significantly higher (91.5+/-14.0 vs 19.0+/-1.6 microm/s, p<0.05). CONCLUSIONS: Bosentan reduces the adhesion of leucocytes in colonic submucosal venules and reduces inflammation in this mouse model of IBD. By inhibiting leucocyte adhesion, a crucial step in the recruitment of leucocytes to the inflamed tissue, bosentan is a potent therapeutic drug in this animal model. Further studies are necessary to investigate the role of bosentan as a novel drug in human IBD.